Heat sterilization validation

Dry heat sterilization validation. The tunnel operations conform to the master validation plan employed at ABC Pharmaceutical Industries. The sterilizing tunnel has undergone installation qualification, operational qualification, and performance qualification. The sterilizing tunnel is revalidated on an annual basis. The sterilization/depyrogenation cycle revalidation data for the tunnel are provided in validation archives. Sterilization validation reports are provided in validation archives. 

As with any sterilization process, the first step in dry-heat sterilizer validation involves qualification of all the equipment and instrumentation used. This step includes examination and documentation of all utilities, ductwork, filters, and control valves or switches for the oven or tunnel unit, and the calibration of the instrumentation used in validating and monitoring the process. The instruments used are as follows ... 

Aseptic BPS machines are subject to steam-in-place sterilization following standard CIP cycles. The SIP cycles are routinely measured by thermocouples located in fixed positions along the product pathway. Validation of SIP cycles should be carried out to demonstrate that consistent sterilization temperatures are achieved throughout the equipment to prove that the system can be effectively sterilized. Validation should also identify suitable positions for routine use, or justify the fixed probe positions already in place. The SIP validation is generally carried out with the help of additional thermocouples and should include the use of biological indicators (appropriate for moist heat sterilization). Test locations should include areas which may be prone to air or condensate entrapment. An accurate engineering line drawing of the system to aid identification of suitable test locations and document test locations selected should be available. 

To provide a written procedure to be used as a guideline for the certification and validation of a dry heat sterilizer... 

Review and verify the washing parameters per the validated cycle dry heat sterilization/depyrogenation. 

The D value is the determining factor if the death rate is, indeed, exponential, an assumption which is not necessarily always valid. Although only conditions which supply a single D value would be sufficient to completely sterilize a solution containing, say, one organism per unit volume, most heat sterilization processes are designed to administer 12D. This is an example of overkill and becomes more evident the fewer organisms there are in the untreated product in the first place. 

These terms heretofore have been applied exclusively in the validation of heat-sterilization processes. The Z value is the reciprocal of the slope resulting from the plot of the logarithm of the D value versus the temperature at which the D value was obtained. The Z value may be simplified as the temperature required for a one-log reduction in the D value ... 

The final step in steam sterilization validation is the establishment of a monitoring program to ensure that the validated cycle remains essentially unchanged in the future. Cycle monitoring usually involves the use of thermocouples to measure heat penetration at the cool spot location and to verify that the design F0 value has been reached. 

V. VALIDATION OF DRY-HEAT STERILIZATION CYCLES A. General Considerations... 

Two types of dry-heat sterilization systems are utilized in the pharmaceutical industry today. They are the conventional hot air oven and the tunnel system. The major difference between the two systems, as far as validation is concerned, is the belt or line speed variable with the tunnel system. 

The key to validating a dry-heat sterilizer is to prove its repeatability. This... 

Table 5 Key Process Features to Control Prior to Validating Dry-Heat Sterilizers ...

Validation studies conducted on dry-heat sterilizers can be divided into two basic components. One component envelops all the physical elements that must be qualified, such as temperature control, air particulate levels, and belt speeds. The other component is the biological constituent, which involves studies that prove that the process destroys both microbial and pyrogenic contaminants. 

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. Trays or racks of ampules or vials should be run through the tunnel and thermocouples placed at strategic locations among the containers. 

D. Biological Process Validation of Dry-Heat Sterilization Cycles... 

The final document will be reviewed and approved by various plant disciplines (engineering, microbiology, production, etc.) before the dry-heat sterilizer is considered fully validated and released for use. 

Ethylene oxide (EtO) has been a sterilant for over 50 years. Yet, while much attention in the literature has been focused on validation of heat sterilization cycles, EtO cycle validation has received relatively little attention. Undoubtedly,... 

Simmons, P. L. Validation of dry heat sterilizers. Pharm Eng 38 (May-July 1981). 

Akers, M. J., Ketron, K., Thompson, B. F value requirements for the destruction of endotoxin in the validation of dry heat sterilization/depyrogenation cycles. J Parenter Drug Assoc 36 23-27 (1982). 

ISO 11134. Sterilization of Health Care Products—Requirements for Validation and Routine Control—Industrial Moist Heat Sterilization. Switzerland (1998). 

It should be noted that bioburden testing (or viable counts) is an integral part of environmental testing, and it is very useful information to complement the effort to validate heat sterilization. The FDA position on terminal sterilization [27] supports the correctness of this statement. 

Parenteral Drug Association. Moist Heat Sterilization in Autoclaves Cycle Development, Validation and Routine Operation. PDA technical report 1, revision, draft 11. Bethesda, MD, May 2001. 

Parenteral Drug Association. Validation of Dry Heat Sterilization Depyro-genation Cycles, technical monograph no. 2, Philadelphia, 1980. 

Colman, L., Helfernan, G. Dry heat sterilization and depyrogenation. In Agalloco, J., Carleton, F. (eds.). Validation of Aseptic Pharmaceutical Processes. 2nd ed. New York Marcel Dekker, 1998. 

Case, L., and Heffernan, G. (1998), Dry heat sterilization and depyrogenation Validation and monitoring, in Agalloco, J., and Carleton, F. J., Eds., Validation of Pharmaceutical Processes Sterile Products, Marcel Dekker, New York. 

Pharmaceutical products can be sterilized by steam sterilization, dry-heat sterilization, filtration sterilization, gas sterilization, and ionizing-radiation sterilization. The USP provides monographs and standards for biological indicators required to test the validity of the sterilization process. These products must also be tested for pyrogens—fever-producing substances that arise from microbial contamination most likely thought to be endotoxins or lipopolysaccharide in the bacterial outer cell membrane. 

Clearly, physical stability is of critical importance for emulsion formulations, and care must be taken to ensure not only that the product itself is physically stable but that any infusion solutions which may be prepared by dilution of the emulsion are also physically stable over the required period of time. In addition, parenteral emulsions should be able to withstand the stresses associated with moist heat sterilization. Alternatively, if this cannot be achieved, it may be possible to prepare an emulsion aseptically from sterile components, provided the process can be suitably validated. For a good introduction to the formulation and preparation of IV emulsions, the reader is referred to Hansrani et al. (1983). 

Parenteral drug products are required to be sterile. There are principally five different ways to sterilize a product. These are steam, dry heat, radiation, gas and filtration. Selection of which method to use is based on the product that requires sterilization. For example, protein-based drugs are heat-sensitive, so the normal means for sterilizing these products is filtration. The rationale for sterilization validation is to show the reduction in microbial load or destruction of biological indicators. 

Sterilization lemperature/time combinations for dry heal are directly analogous to those for sterilization by saturated steam. The options are compendial cycles, overkill, or a validated lO sieriliiy assurance level (SAL). The USP is curiously ambiguous about SALs for dry heat processes although accepting 10 as a standard it stresses that the approach is often to achieve SALs of 10. This is because so many dry heat sterilization treatments arc also intended lo inactivate bacterial endotoxins (see below). 

Sterilization can be achieved by moist or dry heat, by ethylene oxide (or other suitable gaseous sterilizing agent), by filtration with subsequent aseptic filling of sterile final containers, or by irradiation with ionizing radiation (but not with ultraviolet radiation unless the process is thoroughly validated). Each method has its particular applications and limitations. Where possible and practicable, heat sterilization is the method of choice. 

Each heat sterilization cycle should be recorded by appropriate equipment with suitable accuracy and predsion, e.g., on a time/temperature chart with a suitably large scale. The temperature should be recorded from a probe at the coolest part of the load or loaded chamber, this point having been determined during the validation the temperature should preferably be checked against a second independent temperature probe located at the same position. The chart, or a photocopy of it, should form part of the batch record. Chemical or biological indicators may also be used but should not take the place of physical controls. 

Each heat sterilization cycle should be recorded on a time/temperature chart with a suitably large scale or by other appropriate equipment with suitable accuracy and precision. The position of the temperature probes used of controlling and/or recording should have been determined during the validation, and... 

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