validation of autoclave, dry heat sterilizer and membrane filtration

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Slide 1: 

1 Presented By :- Jagani Nayan M. M. Pharm Q.A. ( Sem:III ) Guided By:- Shah Jignesh S. Assistant Professor Department of Quality Assurance S. J. T. P. C. Rajkot 1 Equipment Qualification & Validation of Autoclave, Dry Heat Sterilization And Membrane Filteration A Seminar On

Slide 2: 

Validation may be defined as “ Establishing documented 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.” It has been made mandatory by the regulatory bodies to prove the safety, efficacy, purity & effectiveness of the drug product, medical devices & biologics in the market place & health system. 2

Advantages of Validation : 

Advantages of Validation Reduction in rejections and reworks, Reduction in utility costs, Lower repair costs, Fewer complaints about process related failures, More rapid and accurate investigations into process deviations, More rapid and reliable start-up of new equipment, Easier scale-up from development work, Easier maintenance of the equipment, Improved employee awareness of processes, More rapid automation. 3

Who should do Equipment Validation? : 

Who should do Equipment Validation? The vendor or the user The user has the ultimate responsibility for the accuracy of the analysis results and also for equipment qualification. DQ should always be done by the user. While IQ for a small and low cost instrument is usually done by the user, IQ for large, complex and high cost instruments should be done by the vendor. OQ can be done by either the user or the vendor. PQ should always be done by the user because it is very application specific, and the vendor may not be familiar with these. As PQ should be done on a daily basis, this practically limits this task to the user. 4

Validation Parts: 

Validation Parts Part 1. Overview on qualification and validation Part 2. Qualification of HVAC and water systems Part 3. Cleaning validation Part 4. Analytical method validation Part 5. Computerized system validation Part 6. Qualification of systems and equipment Part 7. Non sterile product process validation 5

Equipment qualification: 

Equipment qualification Equipment qualification / validation includes following things: 6 EQUIPMENT QUALIFICATION DQ (DESIGN QUALIFICATION) IQ (INSTALLATION QUALIFICATION) OQ (OPERATIONAL QUALIFICATION) PQ (PERFORMANCE QUALIFICATION)

Design Qualification (DQ) : 

Design Qualification (DQ) "Design qualification (DQ) defines the functional and operational specifications of the instrument and details for the conscious decisions in the selection of the supplier". The steps that should be considered for inclusion in a design qualification. Description of the analysis problem, Description of the intended use of the equipment, Description of the intended environment, 7

Slide 8: 

Preliminary selection of the functional and performance specifications, Preliminary selection of the supplier, Final selection of the equipment, Final selection of the supplier, Development and documentation of final functional and operational specifications, 8

Installation Qualification(IQ) : 

Installation Qualification(IQ) “ Installation qualification establishes that the instrument is received as designed and specified, that it is properly installed in the selected environment, and that this environment is suitable for the operation and use of the instrument.” The qualification involves the coordinated efforts of – The vendor. The operating department. The project team (which provide input into the purchase, installation, operation and maintenance of the equipment). 9

Operational Qualification (OQ): 

Operational Qualification (OQ) " Operational qualification (OQ) is the process of demonstrating that an instrument will function according to its operational specification in the selected environment ." The proper operation of equipment is verified by performing the test functions specified in the protocol. A conclusion is drawn regarding the operation of equipment after the test functions are checked and all data has been analyzed. 10

Slide 11: 

Following are the contents of equipment operation qualification: 1. Application S.O.P’s, 2. Utilization List, 3. Process Description, 4. Test Instrument Utilized To Conduct Test, 5. Test Instrument Calibration, 6. Critical Parameters, 7. Test Function (List), 8. Test Function Summaries. 11

Performance Qualification(PQ): 

Performance Qualification(PQ) "Performance Qualification (PQ) is the process of demonstrating that an instrument consistently performs according to a specification appropriate for its routine use ". PQ should always be performed under conditions that are similar to routine sample analysis. PQ should be performed on a daily basis or whenever the equipment is being used. In practice, PQ can mean system suitability testing, where critical key system performance characteristics are measured and compared with documented. 12

Slide 13: 

Validation of Autoclave 13

Introduction: 

Introduction Sterile products have several unique dosage form properties, such as Freedom from micro-organisms, Freedom from pyrogens, Freedom from particulates, Extremely high standards of purity and quality; However, the ultimate goal in the manufacture of a sterile product is absolute absence of microbial contamination. 14

Introduction(Con..): 

Introduction(Con..) Three principles are involved in the validation process for sterile product. 1. To build sterility into a product, 2. To demonstrate to a certain maximum level of probability that the processing and sterilization methods have established sterility to all units of a product batch, 3. To provide greater assurance and support of the results of the end product sterility test. 15

D value : 

D value “It is time required for a 90% reduction in microbial population. Quantitative expression of rate of killing of micro organism.” In other words, the D value will be affected by The type of microorganism used as BI, The formulation components and characteristics, The surface on which the micro-organism is exposed, The temperature, gas concentration, or radiation dose of sterilization process. 16

Slide 17: 

Z value Used exclusively in validation of heat sterilization process. Z value is reciprocal of slope of plot of log D verses T at which D value is found i.e. increase in temperature required to reduce D value of organism by 90 % (1 log reduction). F value Used exclusively in validation of heat sterilization process. It is time in min required to kill all spores in suspension at 121 o C. 17

Methods of Sterilization of Products : 

Methods of Sterilization of Products 1.Heat sterilization Moist heat (autoclave), Dry heat oven or tunnel. 2.Gas sterilization Ethylene oxide, Peracetic acid, Vapor phase hydrogen peroxide, Chlorine dioxide. 3.Radiation sterilization Gamma, Ultraviolet. 4. Membrane filteration 18

Slide 19: 

19 Schematic Diagram of Autoclave

Design Qualification: 

Design Qualification 20 Design qualification includes: Facility layout. Utility requirements and specifications. Required capacity of the sterilizer. Type of materials to be sterilized ( Liquids, wrapped ,hollow or porous materials ). Requirement for Prevacuum cycles .

Installation Qualification: 

Installation Qualification 21 The IQ process is intended to demonstrate that as autoclave installed meet all specification installed properly and supporting program ( SOP, Maintenance sheet) are in place. The IQ includes following checks: Supplier or manufacturer name & address shall be checked. Any deviation observed should be informed to the supplier or manufacturer through purchase department for corrective action. Equipment name, make & model no. shall be noted down. In-house Equipment Code No. Shall be allocated to check the Location of installed Equipment Mechanical equipment specification ( chamber, valve, filters, vaccume pump. ) Site specification / utilities. Construction material. Change / spare parts. Operating and maintenance manuals. Preventing maintenance programme .

Operational Qualification: 

Operational Qualification The OQ process intended to demonstrate that components of autoclave operate properly and ready for performance or load testing. OQ includes following checks: Operational tests (Operator modes, emergency stop, doors, display checks, switch, interlock checks and programmable parameter). Saturated steam check. Filter sterilisation. Leak / air removal test. Power loss recovery test. Several utilities need to be verified like clean steam generator, air filteration system, power source and cooling water. 22

Slide 23: 

Selection and Calibration of Thermocouples Thermocouples must be durable for repeated use as temperature indicators in steam sterilization validation and monitoring. Copper constantan wires coated with Teflon are a popular choice as thermocouple monitors. Accuracy of thermocouples should be 0.5°C. Temperature accuracy is especially important in steam sterilization validation. 23

Selection of BI : 

Selection of BI Sr. No Sterilization process Biological Indicator(BI) 1. Autoclave B. steriothermophillus spores B. subtilis var. niger spores B. subtilis, 5230 spores B. coagulance spores Clostridium sporogenes spores 2. Dry heat B. subtilis var. niger spores B. subtilis, 5230 spores 3. Ethylene Oxide B. subtilis var. niger spores 4. Radiation B. pumilus spores Micrococcus radiodurans vegetative cells 24

Performance Qualification : 

Performance Qualification Heat-Distribution Studies Heat-distribution studies include two phases: 1) Heat distribution in an empty autoclave chamber, 2) Heat distribution in a loaded autoclave chamber. The trips where the wires are soldered should not make contact with the autoclave interior walls or any metal surface. 25

Cont…..: 

Cont….. Heat-distribution studies may employ thermocouples at the cool spot in the chamber. The principle is the location of the cool spot and the effect of the load size and/or configuration on the cool spot location. The difference in temperature between the coolest spot and the mean chamber temperature should be not greater than 2.5°C. Greater temperature differences may be indicative of equipment malfunction. 26

Heat-Penetration Studies: 

Heat-Penetration Studies This is the most critical component of the entire validation process. The main purpose is to determine the cold spot inside the commodity. The container cold spot for containers ≥100 ml is determined using container-mapping studies . Thermocouple probes are inserted within a container and repeat cycles are run to establish the point inside the container. 27

Cont..: 

Cont.. Thermocouples will be placed both inside and outside the container at the cool spot location(s), in the steam exhaust line, and in constant-temperature baths outside the chamber. The differnce in temperature will be calculated based on the temperature recorded by the thermocouple inside the container at the coolest area of the load. 28

Microbiological Challenge Studies : 

Microbiological Challenge Studies Microbiological challenges studies are employed to provide additional necessary assurance that adequate lethality has been delivered to all parts of the load. Calibrated BIs used as bioburden models providing data that can be employed to calculate Fo . The microorganisms used to challenge moist heat sterilization cycles are B . steriothermophillus and Clostridium sporogenes . 29

Slide 30: 

After the sterilization cycle is complete, the inoculated items or spore strips are recovered and subjected to microbiological test procedures. Strips are immersed in a suitable growth medium (soybean casein digest medium is typical) and incubated for up to seven days. F 0 value for B. steriothermophillus is 12 min at 121 °C . 30

Filter Evaluation : 

Filter Evaluation Microbial filters are employed on most parts of sterilizers to ensure that loads are not contaminated by air used to vent the chamber as it cools or dries. Product loads are protected from such contamination by their primary containers (vials, bags) and many nonproduct loads are protected by wraps to provide a microbial barrier. 31

Slide 32: 

For filters, two issues are of concern: Sterility and Integrity . If the load will undergo a bioburden cycle, it may be necessary to sterilize the filter in a separate phase of the cycle. To ensure that filters will remain functional under all expected conditions, the integrity tests should be done following the maximum cycle time and temperature. Triplicate studies are recommended. 32

Slide 33: 

Validation of Dry Heat Sterilization 33

Introduction: 

Introduction Mainly three types of dry-heat sterilization systems are utilized in the pharmaceutical industry today. Batch Sterilizer Ovens, Tunnel Sterilizers, Microwave Sterilizers. 34

Slide 35: 

PRINCIPLES OF HEAT TRANSFER AND CIRCULATION: To achieve sterilization or depyrogenation the dry heat process must effectively heat the article and air surrounding the article . In moist heat, the condensation of the steam in sterilizer releases large amounts of heat energy that serves to heat the items in the sterilizer. In dry heat processes the hot air carries significantly less heat energy than an equivalent volume of saturated steam. 35

Slide 36: 

The three main mechanism through which Heat transfer occurs are: Convection, Conduction, Radiation. 36

Design Qualification: 

Design Qualification 37 The DQ includes : Facility layout, decision of batch or continuous process. Utility requirements and specifications. Pressure differential requirements. Required capacity of the sterilizer. Type of materials to be sterilized. Any requirements for presterilization .

Installation Qualification: 

Installation Qualification 38 The IQ includes : Supplier or manufacturer name & address shall be checked. Any deviation observed while following above procedure should be informed to the supplier or manufacturer through purchase department for corrective action. Equipment name, make & model no. shall be noted down. In-house Equipment Code No. Shall be allocated to check the location of installed e quipment.

Installation Qualification: 

Installation Qualification 39 All utility connections such as electrical and HVAC should meet the design specifications . Materials of construction of both the sterilizer and the facility should meet the design specifications . The following pieces of equipment should be calibrated in situ: Temperature sensors and recording devices, Temperature Controllers (in situ ), Pressure gauges, Belt speed controller and recorder, Velometers .

Installation Qualification: 

Installation Qualification 40 1) Structural: Check dimensions, presence of identification plates, correct leveling , proper insulation, presence of seals, and inspect for structural damage . 2) Filters : All filters used within the system must be recorded, such as those used with air (supply, re-circulating) or in other utilities (e.g., steam, water). Some HEPA filters may need to be checked periodically by performing an integrity test / DOP. 3) Electrical: Ensure conformance to National Electrical Code Standards. 4) HVAC: Ensure the system provides the RH, temperature, and pressure differential required.

Slide 41: 

5) Air Supply: Identify source (direct from the HVAC system or room air), duct size, duct material of construction, and air classification. 6) Ventilation: Check that the ventilation exhaust duct exhausts to an appropriate area (not to an aseptic environment), and identify the method used to prevent back-flow. 7) Door Gaskets: Check integrity of gaskets and materials of construction. 41 Installation Qualification

Slide 42: 

8) Heaters: Record the manufacturer’s model number, the number of heating elements, and the voltage of the elements for the heaters. 9) Lubricants: Make certain that any lubricants used cannot contaminate the material being sterilized or depyrogenated. 10) Blowers: The blower must be mechanically sound, the volute in place and correctly balanced, and that the blades rotate in the correct direction. 42 Installation Qualification

OPERATIONAL QUALIFICATION: 

OPERATIONAL QUALIFICATION A. Temperature Monitors : The temperature controllers, recorders, and sensors on the process equipment must be calibrated before the unit can be operated reliably. B. Cycle Timer : The accuracy of the timer must be determined, so that assurance is provided for cycle length. C. Door Interlocks : If a unit is equipped with double doors, the interlocks must operate such that the door leading to the aseptic area cannot be opened. 43

Slide 44: 

D. Heaters: All of the heating elements must be functional. It is preferable to have them monitored continuously with ammeters in order that burned-out elements can be immediately detected. E. Cooling Coils: To enable a faster cool-down cycle, the air is often circulated across coolant coils. F. Belts: The belt speed is a critical operating parameter in continuous hot-air tunnels. Recorders for charting the belt speed are recommended for units with adjustable speed settings. 44

Slide 45: 

G. Particulate Counts: Particulate counts should be checked before and after sterilization to quantitate the particle load. H. Chamber Leaks: The perimeter of the doors for batch sterilizers should be checked for air leakage while operating. 45

A. Batch Oven PQ: 

A. Batch Oven PQ 1. Air balance determination: In an empty oven, data are obtained on the flow rates of both intake and exhaust air. Air should be balanced so that positive pressure is exerted to the nonsterile side when the door is opened. 2. Heat distribution of an empty chamber: Thermocouples should be situated according to a specific predetermined pattern. Repeatability of temperature attainment and identification of the cold spot can be achieved. 46

Slide 47: 

3. Heat-penetration studies: These studies should be designed to determine the location of the slowest heating point within a commodity at various locations of a test load in the sterilizer. Thermocouples are placed in the commodities located in the areas likely to present the greatest resistance to reaching the desired temperature. Minimum and maximum temperatures as defined in the process specifications should be studied. 47

Slide 48: 

4. Mechanical repeatability: During all these studies, mechanical repeatability in terms of air velocity, temperature consistency, and reliability and sensitivity of all the oven and instrumental controls must be verified. 48

B. Tunnel Sterilizer PQ : 

B. Tunnel Sterilizer PQ 1. Air Balance Determination: In this study, items being sterilized are moving exposed to different air systems (e.g., heating zone and cooling zone). Air flow must be balanced in order to provide a gradual decrease in air temperature as items move along the conveyor. In the absence of a critical balance of air dynamics, either the items will not be cooled or they will be cooled too quickly, causing contamination of the entire tunnel area. 49

Slide 50: 

2. Heat-Distribution Studies: Thermocouples used in tunnel sterilizer validation must be sufficiently durable to withstand the extremely high (≥300°C) temperatures in the heating zone area of the tunnel. Heat-distribution studies should determine where the cold spots are located as a function of the width of the belt and height of the tunnel chamber. Peak temperature readings should remain within +/-10°C across the belt for at least three replicate runs. 50

Slide 51: 

3. Heat-Penetration Studies: Prior to microbial challenge testing of the tunnel sterilization, heat-penetration studies must be completed in order to identify the cool spot in the entire load. Three to five replicate runs for each commodity size and every loading configuration should be done using 10 to 20 thermocouples distributed throughout the load. Careful analysis of the temperature data after each run will be valuable in the determination of the cool spot. 51

Slide 52: 

4. Mechanical Repeatability: Tunnel sterilizers must demonstrate mechanical repeatability in the same manner as batch ovens. Air velocity, air particulates, temperature consistency and reliability of all the tunnel controls (heat zone temperatures, belt speed) must be proved during the physical validation studies. 52

5. Biological Process Validation of Dry Heat Sterilization Cycles: 

5. Biological Process Validation of Dry Heat Sterilization Cycles If the dry-heat process is claimed to produce both sterile and pyrogen-free commodities, validation studies must be done using both micro-organisms and microbial endotoxins. The goal is to validate a heating cycle that can produce a 12-log reduction in the biological indicator population. The most widely used biological indicators for dry heat have been spores of B . Subtilis . 53

Slide 54: 

Procedures for the validation of a tunnel sterilization: The overkill approach is selected for the validation study. Select the type of biological indicator to be used. Run a complete cycle using the desired loading pattern. Determine the number of survivors by plate-counting or survivor curve method. Determine the number of spore log reductions (SLRs) 54

6. Endotoxin challenge in Dry Heat Sterilization: 

6 . Endotoxin challenge in Dry Heat Sterilization Inoculate commodity samples with a known amount of endotoxin. (e.g., 10–100 ng Escherichia coli lipopolysaccharide). Thermocouples should be placed in commodities adjacent to those containing endotoxin for temperature monitoring and correlation with LAL test results. Endotoxin destruction should be ascertained at the coolest location of the load. 55

Slide 56: 

Several endotoxin challenge samples should be done per cycle, and the studies must be adequately replicated. Following the dry-heat cycle, aseptically transfer the units containing endotoxin to an aseptic area for extraction procedures. F values required for endotoxin destruction at various temperatures can be determined using a Z value. 56

Slide 57: 

Validation of Membrane Filteration 57

Introduction: 

Introduction 58 Unit operation of filtration is the separation of solids from a liquid by passage through a filter medium. Membrane filtration is used for sterilization of drug product and used in sterilization process. There are two types of filter used in filtration process: Depth filters: Consist of fibrous or granular materials so packed as to form twisted channels of minute dimensions and they are made of diatomaceous earth, unglazed porcelain filter, sintered glass or asbestos. Membrane filters: These are porous membrane about 0.1 mm thick, made of cellulose acetate, cellulose nitrate, polycarbonate, and polyvinylidene fluoride, or some other synthetic material.

Slide 59: 

59 Schematic diagram of Membrane filteration unit

Pre-requisites: 

Pre-requisites 60 In order to efficiently conduct validation of the membrane filtration method, ensure that the following requirements are fulfilled: Validated aseptic facility to carry out the validation All equipments to be used for validation are qualified and operational SOP’s established and followed. All the equipments and culture media required for the validation should be sterile. Clean glasswares with sterile 70% IPA solution.

Slide 61: 

61 Membrane filter:- Sterile individually packed cellulose nitrate or cellulose acetate having average pore size 0.45 m. Validation tasks are to be carried out by trained personnel using techniques and equipment, which minimize the risk of accidental microbial contamination of the test and of the testing environment. Personnel conducting sterility testing or associated aseptic manipulations should wear sterilized garments.

Slide 62: 

62 Identification of c ritical c ontrol / m onitoring parameter Each lot of media used must be tested for its growth promoting qualities as per SOP. During validation carry out environmental monitoring by settle plate and p ersonnel monitoring by swab method as per SOP. If any CFU observed during monitoring on swab method, all CFU must be identified up to species level.

Validation study element: 

Validation study element 63 Physical parameter: Sterilization, Integrity test, Operating condition, Shedding, Microbial challenge test. Chemical parameter: Inertness, Activity/stability, Test for antimicrobial activities, Consistency and reliability. Biological parameter: Endotoxin, Toxicity.

Slide 64: 

64 (1) Sterilization Validation of sterilization method of filter is necessary because filter it self cause contamination of the product. To validate use of sterilizing grade filter it is not only prove that the filter is adequately sterilized but also method does not damage the filter. Most preferred method is moist heat sterilizing. Variable like heat up, cool down, pressure, temperature, time, if it is uncontrolled it lead to filter failure.

Slide 65: 

65 (2) Integrity test It should be non destructive and provide an indication of “ fitness for use ” This include bubble point pressure test, Retention of bacteria. This test of filter should be performed prior to processing and should be performed routinely and conducted after filtration to detect any filter leaks or perforation that might have occurred during the filtration.

Slide 66: 

66 In bubble point test, filter medium wetted with a liquid and test gas pressure is increase until steady stream of bubble appears from tube which is immersed in water. The pressure at which the bubble first appear is recorded as the bubble point pressure.

Slide 67: 

67 (3) Operating condition Time : Long processing time could allow bacteria filtered which have been trapped by the filter. Filter manufacturer can provide the data on the retention tests that have been conducted for specific membrane and generally suggest that filter should retain bacteria excess of 48hr. Filter manufacturer decide the time by performing test.

Slide 68: 

68 Temperature : Manufacture of filter recommended the limit of 20-25c. Pressure : Inlet pressure to the filter must be monitored to ensure that there is no potential for structure damage The differential pressure across the membrane must comply with the filter manufactures recommended limits.

Slide 69: 

69 (4) Shedding: It includes particulates and fiber. Particulates : USP limits when tested by light obscuration method. For LVPs not more than 25 particulates per ml ≥ 10 µm and not more than 3 particulates per ml ≥ 25 µm. For SVPs not more than 6000 particulate per container ≥ 10 µm and 600 particulate per container ≥ 25 µm. Optical microscopy, light obscuration, light microscopic image analysis, scanning electron microscope are used in particulates count. To measure removal of particulates by filter known amount and size distribution of particulates filtered and amount of retention is measured.

Slide 70: 

70 Fiber : Fiber releasing filter may not be used in filtration process unless it is not possible to manufacture such drug product without the use of such filters than use subsequently 0.22 µm mean porosity / 0.45 µm membrane filter.

Slide 71: 

71 (5) microbial challenge test: To ensure filter is not undergoing degradation, deformation or some change under condition of use. Drug product not cause the organism to shrink resulting in non sterilizing condition. Sterilizing filter one that when challenged with 10 7 B. diminuta per cm 2 of filter area will produce sterile effluent. Care should be taken that drug product should not be toxic to organism.

Slide 72: 

72 (6) Filter inertness: There may be extraction and adsorption phenomena occurs. Various technique for determining inertness like compatibility, ph, conductivity, gravimetric extractable, weight change, adsorption, USP oxidizable substance test etc. Stability of the product should not be affected by the filter. In gravimetric extractable test, weight of the extractable are measured when filtered are shocked in ASTM grade water for 24 hr.

Slide 73: 

73 (7) A test for antimicrobial activity Objectives The test is performed to ensure that, any residual of Antimicrobial Activity is satisfactory eliminated by using the steps mentioned in this protocol. An inoculums of viable cells of the specific bacteria and fungi has been passed through the filter, inoculate filter paper in FTM & incubate at 30 to 35 0 C or in SCDM and incubate at 20 to 25 0 C. If conspicuous growth does not occur within 3 days for bacteria and 5 days for fungi, the test procedure indicate that filter have antimicrobial activity.

Slide 74: 

74 (8) Endotoxin Validation must address filter does not add endotoxin to drug product. It depend on quality control process of the filter manufacturer, water used in manufacturing, choice of filter vendor, verification are not done properly. Millipak filter unit contain less than 0.5 units of endotoxin per ml as per USP bacterial endotoxin test.

Slide 75: 

75 ( 9 ) Toxicity A validation study should determine that passage of the drug product through a filter does not cause any toxicological effects. Construction material of filtration system should be non toxic. Manufacture provide relevant test data such a compendial plastic test similar to USP class 6 test for plastics / USP mouse safety test for all construction materials.

Slide 76: 

76 In USP class 6 test was performed to conform that filter are suitable and non-toxic with contact with parenterals . Testing includes systematic and intracutaneous injection as well as intramuscular implantation of filered into mouse. If no toxicity found then filter passes the test.

References: 

References 77 R. A. Nash and A. H. Watcher “ Pharmaceutical process validation ”; Third edition Agalloco James, Carleton J. Fredric “Validation of Pharmaceutical Processes” ; Third edition Pharmaguideline.blogspot.com Berry I.R., and Nash R.A., ”Pharmaceutical Process validation” second edition, revised and expanded; Marcel Dekker series; 83-110. www.fda.gov Wood, R.T; Journal of Parental drug association; volume 34; 286-294 Groves, M.J.; Journal of Parental Technology; 2nd edition; 432 www.milipore.com www.osun.org www.nsdl.niscair.res.in/bitstream

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