Accessed from 113.176.61.212 by gsk on Sun Nov 12 21:40:11 EST 2017 1840 á1229.7ñ Gaseous Sterilization / General Information USP 40 nance, periodic reassessment, and training. When parametric release has not been established, biological indicators positioned within the load are used for routine release of each sterilization load, along with a review of documentation from the sterilizer control system. REFERENCES 1. USP General Chapters—Microbiology Expert Committee. An outline of planned changes to USP á1211ñ Sterilization and Sterility Assurance of Compendial Articles. Pharmacopeial Forum. 2012; 38(2). 2. ISO 11135-1:2007 Sterilization of Health Care Products—Ethylene Oxide—Part 1: Requirements for Development, Valida- tion, and Routine Control of a Sterilization Process for Medical Devices. Geneva: International Organization for Standards (ISO); 2007. 3. ISO 11135-2:2008 Sterilization of Health Care Products—Ethylene Oxide—Part 2: Guidance on the Application of ISO 11135-1. Geneva: International Organization for Standards (ISO); 2008. 4. ISO 10993-7 Biological Evaluation of Medical Devices, Part 7: Ethylene Oxide Sterilization Residuals. Geneva: International Organization for Standards (ISO); 2008. 5. Ethylene oxide, ethylene chlorohydrin, and ethylene glycol proposed maximum residue limits and maximum levels of ex- posure. Fed Regist. 1978; 43(122):27474–27483. 6. Gillis J, Mosley G. Validation of ethylene oxide sterilization processes. In: Agalloco J, Carleton FJ, eds. Validation of Pharma- ceutical Processes. 3rd ed. New York: InformaUSA; 2007. General Chapters á1229.8ñ DRY HEAT STERILIZATION Dry heat sterilization is a process utilized for heat-stable items (glass, stainless steel, nonaqueous liquids, powders, etc.) that are unsuited for steam sterilization because of either an absence of water (nonaqueous liquids and powders) or requirements for absolute dryness following processing (product contact parts for nonaqueous products). Because dry heat relies on air for the transfer of heat to and from the load items, the process takes longer than a steam process for a comparable size item or load. Lengthy heating and cooling periods require that the load items be unaffected by heat over a long period of time and also require the use of the overkill method for cycle development and validation. Dry heat sterilization is typically performed in the range of 160°–190° where the objective is sterilization rather than depyro- genation. (Depyrogenation will be covered separately in Dry Heat Depyrogenation á1228.1ñ). In dry heat sterilization, hot air is in direct contact with the load items (whether wrapped or unwrapped) and transfers some of its thermal energy. Unlike steam sterilization, in dry heat sterilization there is no phase change of the heating medium, and thus heat transfer is less efficient. The items can be stainless steel, glass, ceramic, or other heat-stable materials and may be wrapped or covered with aluminum foil to protect them during pre- and postprocess handling. Dry heat sterilization is commonly used for heat-stable materials (e.g., petrolatum or powders). The limited heat transfer capacity of air requires that items in the oven be placed in locations that were confirmed to be acceptable during the validation effort. Manufacturers should exercise caution with varying load sizes because in some instan- ces (resulting from system design and control probe positioning) minimum load sizes may present a worst case. STERILIZATION CYCLE CONTROL Process equipment for dry heat sterilization is controlled by calibrated temperature sensors. During the exposure portions of the cycle, attainment of a minimum dwell time at a predefined temperature is used to document process lethality. Cycle effica- cy for dry heat sterilization customarily is measured using FH, which typically is defined as the amount of time the load receives the equivalent of exposure at 170°. The FH approach is used to compare sterilization processes that operate at varying temper- ature conditions to a single standard. The process lethality at temperatures other than 170° can be calculated to determine lethality equivalent to that provided at 170°. Sterilizer control systems must deliver conditions within a predefined time–tem- perature or FH range. Simple mathematics can be used to calculate the total lethality over the course of the process. For the specific reference temperature of 170° and a z-value (for definitions see Steam Sterilization by Direct Contact á1229.1ñ) of 20°, the FH calculation can be determined by the following equation: FH = accumulated lethality t2 = end time t1 = start time T = temperature Official from August 1, 2017 Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved. 61. The oven or tunnel should be evaluated to determine the range of temperatures within the system. It may be possible to validate maximum and minimum loads as de- termined by either the number of items or their mass within the oven. Official from August 1. All rights reserved. End users should determine the population and resistance of their biological indicator used when inoculating their own items. Biological Indicators The biological indicator (BI) for dry heat sterilization is Bacillus atrophaeus (ATCC 9372). For each load item. In some companies.212 by gsk on Sun Nov 12 21:40:11 EST 2017 USP 40 General Information / á1229. That objec- tive can be demonstrated by attaining any of the following: a defined minimum lethality. ensuring reproducibility of operation over time and assurance that the sterilization process is constantly and accurately performed. Empty Chamber Temperature Distribution The equipment should be evaluated for empty chamber temperature distribution. 2017 Copyright (c) 2017 The United States Pharmacopeial Convention. The acceptance criteria for empty chambers can vary with the equipment capabilities and customary use. the greater lethality provided by the overkill method clearly is justifiable. and the cycle parameters should be determined to ensure ade- quate lethality across the expected load. VALIDATION OF DRY HEAT STERILIZATION Because dry air has limited heat capacity and dry heat conditions are more variable than those encountered with other ther- mal sterilization methods. Information from the load mapping is used to adjust cycle timing to ensure appropriate lethality. a defined set of method conditions. Overkill sterilization can be defined as a method in which the destruction of a high concentration of a resistant microorgan- ism supports the destruction of reasonably anticipated bioburden that could be present during routine processing. The major use of qualification of the sterilizing equipment is to provide a baseline for pre- ventive maintenance and change control. Load and component mapping ensures that all load items attain the re- quired temperature. Load Mapping Fixed loading patterns for dry heat sterilization in batch ovens are preferable because the limited heat capacity of the air allows substantial temperature differences across the load. or confirmation of minimum log reduction of a resistant biological indicator. System control must consider the relationship between load position and size relative to temperature control locations. During component map- ping load items should be prepared and oriented in a manner that is consistent with how they will be processed.176. This is particularly important in powder sterilization. The validation requirements for the overkill method are less onerous than those of the other sterilization approaches. but it is typically less uniform than observed in steam sterilizers. If spores are used as intended by the BI manufacturer. .8ñ Dry Heat Sterilization 1841 Accumulation of the lethality (FH) for the sterilization process across the entire cycle (heat-up and cool-down segments inclu- ded) includes the contribution of those segments and allows the cycle to be defined by a targeted lethality rather than by a time at a defined minimum temperature. a thermophilic spore-former with high resistance to dry heat. manufac- turers should establish the ability of heat to penetrate the items or containers and to bring them to the required temperature. These studies can be performed in a laboratory setting and need not be repeated when the same item is sterilized in other equipment. Thermocouples should be placed into direct contact with the item(s) being evaluated. Loading in a continuous tunnel process is typically well defined by the limitations of the conveying system.Accessed from 113. analysts routinely validate their dry heat sterilization procedures using the overkill method as defined in Sterilization of Compendial Articles á1229ñ. The spore challenge is placed on a substrate positioned within the load or on a load item. Component Mapping Load items that are complex and feature enclosed volumes and product contact surfaces should be subjected to component mapping to determine internal cold spots. the population and resistance information provided by the vendor can be used. Be- cause the load items can withstand substantial amounts of heat without adverse consequence. equipment qualifica- tion is separated into installation qualification and operational qualification or is lumped together under a joint terminology of installation/operational qualification. Biological indicators are not required dur- ing the evaluation of empty chamber temperature distribution. Equipment Qualification Equipment qualification is a predefined program that focuses on the sterilizing equipment to confirm that it has been prop- General Chapters erly installed and operates as intended before evaluation of the sterilization process. 8ñ Dry Heat Sterilization / General Information USP 40 Heat Penetration and Microbiological Challenge The core of the validation activity is the confirmation of acceptable heat penetration using temperature measurements and microbial challenges. Accessed from 113. The princi- pal usage of physicochemical integrators and indicators is to provide a rapid means of confirmation of sterilization cycle com- pletion. Sterilization of health care products—Radia- tion—Part 3: Guidance on dosimetric aspects (1). . which results in a measurable value that can be correlated to microbial lethality. Aside from radiation sterilization where dosimetric data is accepted as definitive they should not be used as the sole proof of cycle efficacy (see Radiation Sterilization á1229. change control. General chapter Sterilization of Compendial Articles á1229ñ details the general practices that are appropriate for all sterilization systems. If the microbial and physical measurements do not correlate. Proof of cycle efficacy is provided by replicate studies in which the BIs are killed and the physical measurements correspond to the expected values of time–temperature or FH. REFERENCES General Chapters 1.61. The physicochemical indicator provides an immediate visual confirmation that an item has been exposed to a steriliza- tion process. Pharm Forum. USP General Chapters—Microbiology Expert Committee. á1229.10ñ). This is especially important with single door sterilization chambers where a potential mix-up of nonsterilized and steri- lized items is more likely. physical measurements. Performance of the sterilization apparatus must be ascertained from records generated by calibrated instru- ments (temperature. Thermocouples should be placed into direct contact with the item(s) being monitored. and should not alter the strength. ongoing process control. Physicochemical integrators for radiation sterilization are designed to react predictably to the delivered radiation dose and can provide primary evidence of sterilization process effectiveness. 2012. The integrator or indicator should be positioned such that it does not alter the effectiveness of the sterilization process. it must be subject to formalized controls that keep it in a validated state over time.212 by gsk on Sun Nov 12 21:40:11 EST 2017 1842 á1229. Integrators or indicators should not interact physically or chemically with any container or product when placed in the sterilizer load. ROUTINE PROCESS CONTROL As with all sterilization processes. exposure time. as applicable). gas concentration. PHYSICOCHEMICAL INTEGRATORS A physicochemical integrator is defined as a device that responds to one or more sterilization process critical parameters. 38(2). Physicochemical integrators require precautions for use and the appropriate interpretive criteria to define their performance characteristics. All rights reserved. after the dry heat sterilization process has been validated. Performance standards both within and between lots of physicochemical integrators or indicators from a given manufacturer should be consistent. and others. This is accomplished by a number of related practices that are essen- tial for the continued use of the process over an extended period of time. The essential practices to maintain validated status include calibration. Official from August 1. An outline of planned changes to USP á1211ñ Sterilization and Sterility Assurance of Compendial Articles. The integrator can demonstrate only inadequate or adequate exposure to a combination of sterilization parameters. pressure. The use of dosimeters in radiation sterilization cycle devel- opment and routine process control is addressed in ANSI/AAMI/ISO 11137-3. manufacturers should conduct an investigation and should take corrective action to rectify the discrepancy.9ñ PHYSICOCHEMICAL INTEGRATORS AND INDICATORS FOR STERILIZATION INTRODUCTION Physicochemical integrators provide some assessment of sterilization process efficacy and may be used in cases where valida- tion of a sterilization process is not required—an exception is the validation and monitoring of radiation sterilization with dos- imetry. Thermocouples and BIs are placed within the load items at the locations determined during the compo- nent and load mapping to present the worst case. 2017 Copyright (c) 2017 The United States Pharmacopeial Convention. pre- ventive maintenance.176. and/or cumulative lethality. The manufacturers of physicochemical inte- grators should provide data to demonstrate that the labeled performance characteristics tests of the integrators are met. and periodic reassessment and training. temperature. physical integrators and indicators. This study custom- arily is performed slightly subminimal to the lower specification limits for time. quality. or purity of the sterilized article.