DEPYROGENATION TUNNEL VALIDATION PDF

Dry heat depyrogenation is dependent upon two parameters: time and temperature. Depyrogenation processes typically operate at a range of temperatures from approximately up to about The pyrogenic agents that are of greatest concern in healthcare are bacterial endotoxins, found in the outer cell walls of Gram-negative bacteria. The inactivation of bacterial endotoxins depyrogenation by dry heat has been studied extensively and has been shown to follow first order kinetics. The well-defined kinetics of inactivation makes it possible to predict the efficacy of dry heat processes operating at different times and temperatures.

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Dry heat depyrogenation is dependent upon two parameters: time and temperature. Depyrogenation processes typically operate at a range of temperatures from approximately up to about The pyrogenic agents that are of greatest concern in healthcare are bacterial endotoxins, found in the outer cell walls of Gram-negative bacteria. The inactivation of bacterial endotoxins depyrogenation by dry heat has been studied extensively and has been shown to follow first order kinetics.

The well-defined kinetics of inactivation makes it possible to predict the efficacy of dry heat processes operating at different times and temperatures. It is important to consider that the range of temperatures used for dry heat depyrogenation overlaps the upper range of temperatures used for dry heat sterilization see general chapter Dry Heat Sterilization However, the temperatures most commonly used for inactivation of endotoxins are considerably higher than those used for sterilization.

This is because bacterial endotoxins are more resistant to the effects of dry heat than are even the most heat-resistant bacterial spores.

Therefore, dry heat processes that deliver a combination of temperature and exposure time sufficient for achieving typical endotoxin inactivation targets can also be counted upon to reliably sterilize materials.

This chapter provides an overview of the process of dry heat depyrogenation, its control, and validation. Batch ovens are used for the depyrogenation of not only product containers, most often glass, but also other heat stable product contact parts or laboratory equipment. Continuous tunnels, on the other hand, are used primarily to depyrogenate glass product containers.

Batch Ovens Circulating heated air is used to heat the load items, which may be individually covered or wrapped in a material that is unaffected by the temperature used, or placed in a lidded container to protect them during pre- and post-process handling. When depyrogenation and sterilization are to be achieved in the same process, air supplied to the oven is passed through one or more high efficiency particulate air HEPA filter s to maintain sterility within the oven after completion of the dwell period.

These forced air ovens typically operate at a positive air pressure differential relative to the surrounding room and the heated air is often recirculated through a battery of heaters and the HEPA filter s to improve thermal efficiency.

This design results in particulate air quality that can meet ISO 5 requirements to reduce particulate matter and microbial contamination risk throughout processing. Caution should be exercised in defining variable load patterns as minimum load sizes may result in inadvertent slower heating of the load and greater temperature variability. Smaller facilities may use a single door oven, but the principles of operation and validation are the same as with larger double door production units.

The important batch oven process variables are set-point temperature, duration of dwell period, load type and configuration, airflow characteristics, and container size. Continuous Tunnels The use of tunnels for dry heat depyrogenation of glass containers on a moving conveyor allows for substantially higher throughput and packing densities than the batch process and is ordinarily linked directly to a filling system. Tunnels typically use forced heated air systems or radiant IR systems that recirculate air through a battery of HEPA filters.

Load items in tunnels are unwrapped and placed directly on the moving belt. Depyrogenation tunnels have separate zones for heating and cooling, allowing for continuous in-feed and discharge at temperatures appropriate for production purposes. The tunnel is maintained at constant airflow and temperature conditions during use, and as glass passes through the tunnel it is heated to depyrogenating temperatures and cooled before exiting.

Although the conditions within the tunnel are essentially constant and well controlled, the temperature of the glass as it passes through the tunnel on the conveyor will change with its location. Dwell time is controlled by adjusting the conveyor speed, 1 which in the depyrogenation tunnel is the process parameter that governs exposure time. The air in the tunnel is most commonly heated using electrical coils but other heat sources, such as infrared or high-pressure steam, have been used.

For energy conservation, heated air in depyrogenation tunnels is often recirculated. The limited heat capacity of dry air results in relatively slow heating and cooling of the load items. Variability in temperature distribution in dry heat ovens and tunnels is typically much higher than that observed in moist heat systems. Packing and thermal mass will also play critical roles in temperature management. Caution must also be exercised with varying load mass and distribution as in some instances resulting from oven design, air flow characteristics, and control probe position minimum load sizes may result in process variability.

The exposure portion of the process is designed to attain a minimum dwell time at a predefined minimum temperature ensuring that depyrogenation conditions are adequately uniform. The defined dwell time is determined by using measurement devices e. The inactivation of bacterial endotoxins by dry heat involves the control of only two parameters: time and temperature. Together they provide dosimetric measurement of the dry heat depyrogenation process. The simplicity of process control for these parameters provides a predictable depyrogenation effect; thus it is not necessary to use an indicator such as endotoxin to establish process efficacy.

The dosimetric measurement for dry heat depyrogenation processes is the FH unit. The FH-value enables the integration of temperature over the process duration time. By convention the rate at which depyrogenation destruction rate D-value varies as a function of temperature change is defined as the z-value. For the purposes of this chapter, 50 is used as a standard z-value 1,2.

A widely used dry heat depyrogenation process is for 30 min, which is equivalent to a total FH of Studies on the resistance D-value of endotoxin to dry heat have been published and have reported considerable variability 1,2,3,4.

The D-value must be referenced to a specific depyrogenation temperature and is by convention the amount of time required to reduce endotoxin concentration by 1 log. Therefore, a process demonstrating an FH of 30 min during the exposure period can be considered extremely safe in terms of pyrogen inactivation. Given the frequency with which processes that yield an FH of 30 min have proven to be safe and effective, USP considers any process that yields an FH NLT 30 min during the exposure period to require no endotoxin challenge.

For the purposes of this chapter, only time at or above is considered in the FH accumulation, which adds an additional margin of safety because heat-up and cool-down add to the accumulated FH.

Given the much higher Dvalues for endotoxin as compared to intact microorganisms, these conditions are also sterilizing, provided appropriate precautions are made so as to maintain sterility of treated materials from the end of the process until their use. The FH approach is used as a means to compare dry heat depyrogenation effects produced by processes that operate at varying temperature targets.

Basic mathematics can be used to calculate the depyrogenation effect produced at temperatures other than to determine equivalence to that provided at Many commercial data loggers are equipped with software that enables them to make this calculation and integrate the total FH accumulated during a process. The FH calculation is used during initial validation, validation maintenance, and change control. The mathematical principles of the FH calculation are essentially the same as those used to calculate lethality F0 values in moist heat sterilization.

Times and temperatures used for the purpose of destroying bacterial endotoxins can result in extreme challenges to material integrity and stability. Equipment Qualification EQ EQ is a predefined program that focuses on the processing equipment to confirm that it has been properly installed and operates as intended prior to evaluation of the process.

Equipment qualification provides a baseline for preventive maintenance and change control assuring reproducibility of equipment operation over time.

Empty Chamber Temperature Distribution for Ovens The oven should be evaluated for empty chamber temperature distribution. This is assessed by measurement of temperature at each corner of oven, near the controlling probe s and other locations as justified. Differences in the cycle dwell period can be discounted in this evaluation, as only the shortest dwell period need be evaluated.

The evaluation is best performed over the last few minutes of the dwell period once the system has fully equilibrated. Depyrogenation ovens that are located at floor level may have even greater ranges in temperature. Endotoxin inactivation studies of any kind are not required in the evaluation of empty chamber temperatures. Temperature Distribution in Tunnels While these studies are often done, they are of limited value. Unloaded depyrogenation tunnels will always produce far more variability in temperature attained and distribution than will a fully loaded tunnel.

This is because the absence of glass on the conveyor belt results in heated airflow that is too unidirectional to allow for optimal heat transfer. Therefore, for depyrogenation tunnels, temperature studies under only fully loaded conditions are indicated.

Component Mapping The ability of heat to penetrate load items and to bring them to the required temperature should be determined. Load items that are complex, with enclosed volumes and product contact surfaces that must be depyrogenated, should be subjected to component mapping to determine internal cold spots.

All load items should be prepared and oriented in a manner consistent with how they will be processed. Mapping of glass components to be processed in tunnels is not necessary; all monitoring of temperature is accomplished with probes placed at the bottom of the container. Load Mapping Fixed loading patterns are necessary in oven depyrogenation because of the limited heat capacity of the air; fully packed conditions because of their greater mass ordinarily result in the best process temperature uniformity.

Load mapping assures that items placed throughout the load attain the required depyrogenation conditions. Information from the load mapping is used to adjust cycle timing to assure appropriate efficacy across the entire load. It may be possible to validate maximum and minimum loads as determined by either the number of items or their mass. Load mapping for tunnels is not particularly useful, as load density based on container size may vary substantially in actual use due to intermittent feeding of the tunnel, and loads that have substantial gaps in the glass typically exhibit higher temperatures.

The operation of the tunnel is such that the initial entry of the glass pack and the exit of the last glass in the system at the end of the operation routinely show the highest temperature variability and the lowest depyrogenation effect. Tunnel designs or equipment fixtures that create air turbulence at the front and end of the glass pack can minimize this condition.

Glass temperature can be assessed using sets of calibrated thermocouples i. Thermocouples should be placed into direct contact with the item s at the bottom of the container. Temperature and exposure time, which are the only two critical depyrogenation parameters, should be measured with each load in an oven.

The accumulated depyrogenation effectiveness can easily be measured for each process cycle where a depyrogenation tunnel is used. The overall depyrogenation effectiveness of the cycles or processes can easily be determined on each event by using the FH value to ensure that safe depyrogenation conditions were achieved. Where direct assessment of FH is not possible, assuring that the temperature and exposure time conditions were met results in an equivalent confidence that the depyrogenation system operated in a validated state of control.

General chapter Depyrogenation details the general practices that are appropriate for all depyrogenation systems. This is accomplished by a number of related practices that are essential for the continued use of the process over an extended period of time.

The essential practices to maintain validated status include calibration, physical measurements, periodic endotoxin assessment on incoming materials, ongoing process control, change control, preventive maintenance, and periodic reassessment and training. Dry heat destruction of lipopolysaccharide: a mathematical approach to process evaluation. Appl Environ Microbio. J Parenteral Sci Technol. Tsuji K, Harrison S. Dry heat destruction of lipopolysaccharide: dry heat destruction kinetics.

Ludwig J. Avis KE. Dry heat inactivation of endotoxin on the surface of glass.

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The unit is supplied with heat resistant HEPA filters Operational Qualification In addition to the common requirements outlined in the "General" section, the tunnel differential pressures prevent air travel from the dirty to clean areas. Rate of speed, minimum, maximum and nominal, will be measured and verified. Physical handling of containers will be monitored. No containers should be damaged, none hung up, or dislodged. The tunnel will be temperature mapped to demonstrate consistency. Note: Infrared tunnels, which heat components, not the air, cannot be mapped in the absence of bottles. The mapping is therefore performed in the PQ.

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Depyrogenation

In the case of a washing machine, is the effectiveness of the internal washing of the bottles while in the case of a depyrogenation tunnel is the effectiveness of depyrogenation of bottles: for both the test the acceptance criteria is at least 3 log reduction of the initial contamination. If we consider that all pharmaceutical vials used for the parenteral drug can be assimilated to the vial in figure 1, it is possible to perform some consideration explained in the following paragraph. Washing machine Taking into consideration the washing of vials, you could group all the bottles in groups associated with the size of the cups that are connected and, for each group, define a wash cycle time of spraying, the water quantity that reach the criterion with the bigger internal surface of the bottle. Once validated the cycle according to the validation protocol generally with three replicates for the bottle with larger surface, will be automatically "validated" all the other bottles having a less internal surface because, if the cycle does not change and even the storage conditions of the bottles, there are not a technical reasons to say that the cycle is not able to obtain the same results with a bottle whose surface is found to be lower.

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Get on-site validation and qualification service. We have trained and highly skilled validation engineers. The temperature used depends on the duration of the process. Gravity or mechanical heat convection can be used for this process. The former uses the natural interaction between air and different temperatures, and the latter produces a specific flow of air with the help of a blower. Depyrogenation is mainly used in the sterilization of vials for aseptic filling. The process is also useful to sterilize assembled and packaged materials, since heat conduction does not require the contact of the product with steam or water.

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