Content: • Definition of Sterilization and Depyrogenation Dry Heat Depyrogenation Theoretical requirement: . continuous (Tunnel) sterilizer validation is. device is a depyrogenation tunnel, the rate of speed (e.g., minimum, As part of the validation, normally at the performance qualification stage, depyrogenation devices are . Guideline for industry, Sterile Products Produced by Aseptic. Beyond the usual engineering aspects of validation with regard to Depyrogenation devices, such as tunnels, are used in the Guideline on Test Method for Environmental Monitoring for Aseptic Dispensing,
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PDA Validation of Dry Heat Processes Used for Depyrogenation and. Sterilization Technical Report Team . Loaded Tunnel Temperature Distribution Validation Protocol for Sterilization and Depyrogenating Tunnel used in sterile be compiled to evaluate ability of the sterilization and depyrogenation tunnel to. Guidance Sterilization or Depyrogenation Validation - Non Product For continuous belt depyrogenation tunnels, thermocouples should be fed into.
Position the sampling probe towards airflow at work level and Sample at least 3 cycles for each location. Each cycle should be Approx. Paste the printouts generated by the particle counter on A4 page and shall be photocopied. Verify the printouts for all calculations and acceptance criteria as mentioned below.
Attach the photocopies of the same to the annexure —1. Attach the calibration certificate of Particle Counter. Acceptance criteria: All the readings of test should pass the below mentioned criteria.
Ensure that the entire conveyor area to be covered during mapping. The placement temperature sensors in empty chamber. The natural progression of sensor on the conveyor that occurs during actual running of the tunnel shall be simulated.
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Record the position of temperature sensors in representative schematic form. Connect the probes to suitable data logger, which can scan and print the actual temperatures with respect to time.
Start the data logger to record the actual temperatures within the sterilization zone with respect to time. Collect print out from the printer of the tunnel control panel and attach to the annexure-1 with attachment No. Download the data from the data logger into the computer for data analysis and printing.
Review and attach the printouts with attachment No. Repeat two more consecutive runs to demonstrate sterilization cycle reproducibility. Acceptance criteria There should be uniform temperature distribution across the conveyor belt during the hold period.
Note: The temperature sensors shall be placed in straight line across the belt, tied to the SS wire, during heat distribution studies. Empty glass vials as required shall be fed to the tunnel sterilizer from the vial washing machine. Both the vials with endotoxin and temperature sensor must be placed side by side.
The placement Endotoxin indicator vials and temperature sensors in empty vials. The vials shall not be tied with wire to keep together. The natural progression of vial on the conveyor that occurs during actual running of the tunnel shall be simulated.
Record the set parameters for the sterilization cycle to be operated during the test. Record the position of the vials with temperature sensors and vials with Endotoxin in representative schematic form. During the validation run inspect the vials in the tunnel sterilizer for the following parameters: Look through the glass window of the tunnel to following shall be verified Position of the vials on the conveyor. Movement of the vial on the conveyor belt.
To inspect the incoming vials to the in-feed turntable of the powder filling machine. Presence of any spot on sterilized vial surface. When the sterilization cycle completes: When all the vials, attached with temperature indicating probe and endotoxin indicator vials, and vials crosses the cooling zone, Stop the conveyor belt of sterilizing tunnel, switch off the data logger and pull out the probes.
Collect print out from the printer of the tunnel control panel, review and attach to annexure-1 with attachment No. Review and attach the printouts to annexure-1 with attachment No. Wrap the exposed endotoxin indicator vials with sterile aluminium foil in filling room and identify suitably.
Send the exposed vials to Microbiology lab to estimate the quantity of the residual endotoxin as per the SOP. Record the results in the annexure FH value should be more than the value calculated in the FH value calculation sheet proving the sterility assurance by log reduction.
Using assumed D-value and worst case heat resistant spore population The temperature distribution is uniform throughout the sterilization period i. An example is 0. The following are various mechanisms min.
This is often coupled with 0. It will block USP reverse osmosis RO can be used to peroxide. The physical variations e. Alternatively, some studies have shown ing that many of the principles might apply to other that autoclaving for prolonged periods of time or primary packaging materials providing that they can at higher temperatures can be effective at reducing withstand high temperatures.
This process both sterilizes and de- centrations of endotoxin and is applied to non-heat pyrogenates and is mainly used for glass components. For example, the European Phar- duction transfer of heat from adjacent molecules , macopoeia in chapter 2.
Performance Qualification Protocol of TUNNEL STERILIZER
The qualification of a depyro- based on the non-linearity of the thermal destruction genation device operating by dry heat involves chal- curve. Endotoxin destruction at low temperature is of lenging the device, such as a depyrogenation tunnel, the second-order These parameters include laminar airflow controlled by high-efficiency particulate air HEPA filters, with Depyrogenation by Dry Heat—Case Study a specification for air velocity and particulates.
Where The following is a case study of depyrogenation of glass the device is a depyrogenation tunnel, the rate of speed vials in a hot air tunnel sterilizer. The key function for depyro- facture of pharmaceutical products and is distinct genation is temperature control. Such depyrogenation from sterilization. Sterilization refers to the destruction devices require qualifying as part of validation.
This is of living cells. However, the process does not neces- performed along the familiar lines of design qualifica- sarily destroy microbial by-products and toxins.
En- tion, installation qualification, operational qualifica- dotoxin is one toxin that is extremely heat stable and tion, and performance qualification, as well as annual is not destroyed by standard sterilization cycles e.
A depyrogenation study is a test of the autoclaving. If only sterilization is required to be dem- physical capabilities of a device to depyrogenate an ar- onstrated, this can be achieved using biological indica- ticle or device.
QUALIFICATION AND VALIDATION OF DEPYROGENATION TUNNEL: A REVIEW
It is demonstrated by physical measure- tors impregnated with endospores from a heat resistant ments including temperature and biological using bacteria e. The biological test is the concern dry heat] or Geobacillus stearothermophilus [often used of this paper. The preparation mance qualification, firstly involves running the de- used is a freeze-dried extract from the Gram-negative vice with a full set of containers in normal operation.
The prepa- Simultaneously, the depyrogenation device is tempera- ration is similar to the control standard endotoxin CSE ture mapped using thermocouples. The thermocouples used for routine LAL testing, although the concentra- indicate where the cold spots i.
The run is then re- As indicated earlier, the mechanism for endotoxin peated using endotoxin challenges at these colder areas, destruction by depyrogenation is not fully understood alongside thermocouples.
One problem to consider, be- Many tunnel This is a logarithmic reduction until three logs of endo- sterilizers have a capacity for many thousands of bottles.
The number used will be based on a log-step rate. This is partially the reason why the crite- the size of the depyrogenation device.
Typically, five to ria for a successful depyrogenation validation are set at a ten challenge vials are sufficient to assess the depyroge- minimum of three-logs to provide an over-kill and com- nation capabilities of the device being tested. The time and temperature combination is of im- dotoxin challenges: portance.
The second approach, Although the first ever depyrogenation studies were due to the endotoxin being contained in a vial of a dif- conducted in the early s using rabbits to detect re- ferent size and invariably of a different type of glass , is sidual pyrogens, it is not considered ethical, or scien- less of a representative challenge.
The second method is tifically valid, to use the rabbit test for depyrogenation not often accepted by regulatory authorities. Any of the three established LAL methods can In both cases the endotoxin challenge is typically be used to conduct a depyrogenation study: gel-clot, Endotoxin Units EU or greater. The level of the turbidimetric, and chromogenic. However, where pos- challenge is determined by using control vials that are sible, the gel-clot method is not recommended because not subjected to the depyrogenation cycle.
These are of the large number of dilutions required. It is not necessary to recover all of the by the US Food and Drug Administration and pur- endotoxin from the control vials, and it is acknowledged chased with a certificate of analysis for the lot of lysate that recovering endotoxin is difficult.
It is only necessary to recover a level endotoxin. This potency is used to convert the labeled of endotoxin to show that the necessary log reduction weight of the endotoxin expressed in nanograms into has been achieved.
The amount of water should be suf- per device recovery, the three-log reduction would have ficient to cover the base of the device and allow rins- been achieved. Nevertheless, some level of laboratory ing. The vials require different techniques in order to competence should be demonstrated, in that the level remove the endotoxin from the glass surface.
These are of endotoxin recovered from control vials can be done typically variations of vortex mixing and ultrasonica- so reproducibly. The actual times required for optimal endotoxin When carrying out a depyrogenation study, pyrogen- recovery will need to be assessed by the user.
A dis- free pipettes and glassware must be used throughout. The vials that are challenged with endo- dard series consisting of a minimum of three-log con- toxin require preparing the day before the validation centrations of endotoxin. The standard series should be run in order to allow for the endotoxin to dry onto the prepared using the same lot of endotoxin used to chal- base of the vial.
The endotoxin should be applied The control vials require dilution prior to testing. The to the base of the vial and the vials dried so that there level of dilution will depend upon the expected level of is no visible endotoxin under a unidirectional airflow endotoxin to be recovered. Negative control vials are cabinet to protect the exposed vials from contamina- also required. Normally, two types of negative controls tion.
There will be a degree of loss through evaporation, are used. The first set is uninoculated vials, which are although the extent of this is assessed through the re- not put into the depyrogenation device.
The result from covery from the control vials.
Typically, a 0. The second set consists of vials that have passed onto the surface of the glass.
In order to increase the re- through the depyrogenation device. These are tested in covery of endotoxin, Novitsky 23 recommends freeze- the event that the elevated temperature inside the de- drying the challenge rather than air-drying , although pyrogenation device has resulted in the leeching of any this requires specialized equipment that is not available interfering substances that might inhibit the LAL assay.
Other techniques include using an Both types of negative controls should show a low level elevated temperature to increase the rate of drying.
The of residual endotoxin of below the calculated three-logs. In order to claim depyrogenation, challenge level of endotoxin.The natural progression of sensor on the conveyor that occurs during actual running of the tunnel shall be simulated. These are tested in covery of endotoxin, Novitsky 23 recommends freeze- the event that the elevated temperature inside the de- drying the challenge rather than air-drying , although pyrogenation device has resulted in the leeching of any this requires specialized equipment that is not available interfering substances that might inhibit the LAL assay.
The second method is tifically valid, to use the rabbit test for depyrogenation not often accepted by regulatory authorities. The run is then re- As indicated earlier, the mechanism for endotoxin peated using endotoxin challenges at these colder areas, destruction by depyrogenation is not fully understood alongside thermocouples.
Sterilization refers to the destruction devices require qualifying as part of validation. Set the particle counter in ISO mode. My question is, should the glass vials selected to carry the thermosensors be on the same line or theses glass vials should be selected randomly or based on a specific load schedule although we are referring to a tunnel?
Both the vials with endotoxin and temperature sensor must be placed side by side.
When all the discrepancies are satisfactorily resolved or an approved action plan is developed which ensures that the discrepancy will be resolved. You may want to change the belt speed based on these values, and determine your edge of failure.