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1840 1229.7 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 ChaptersMicrobiology Expert Committee. An outline of planned changes to USP 1211 Sterilization and
Sterility Assurance of Compendial Articles. Pharmacopeial Forum. 2012; 38(2).
2. ISO 11135-1:2007 Sterilization of Health Care ProductsEthylene OxidePart 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 ProductsEthylene OxidePart 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):2747427483.
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

1229.8 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 160190 where the objective is sterilization rather than depyro-
genation. (Depyrogenation will be covered separately in Dry Heat Depyrogenation 1228.1). 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 timetem-
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 1229.1) of 20,
the FH calculation can be determined by the following equation:

FH = accumulated lethality
t2 = end time
t1 = start time
T = temperature

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USP 40 General Information / 1229.8 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.

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, analysts routinely validate their dry heat sterilization procedures using the overkill method as defined
in Sterilization of Compendial Articles 1229.
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. That objec-
tive can be demonstrated by attaining any of the following: a defined minimum lethality; a defined set of method conditions;
or confirmation of minimum log reduction of a resistant biological indicator.
The validation requirements for the overkill method are less onerous than those of the other sterilization approaches. Be-
cause the load items can withstand substantial amounts of heat without adverse consequence, the greater lethality provided
by the overkill method clearly is justifiable.

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. In some companies, equipment qualifica-
tion is separated into installation qualification and operational qualification or is lumped together under a joint terminology of
installation/operational qualification. The major use of qualification of the sterilizing equipment is to provide a baseline for pre-
ventive maintenance and change control, 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. The oven or tunnel should be evaluated
to determine the range of temperatures within the system, and the cycle parameters should be determined to ensure ade-
quate lethality across the expected load. The acceptance criteria for empty chambers can vary with the equipment capabilities
and customary use, but it is typically less uniform than observed in steam sterilizers. Biological indicators are not required dur-
ing the evaluation of empty chamber temperature distribution.

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. This is particularly important in powder sterilization. For each load item, 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. During component map-
ping load items should be prepared and oriented in a manner that is consistent with how they will be processed.

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. 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. Loading in a continuous tunnel process is typically well
defined by the limitations of the conveying system. Load and component mapping ensures that all load items attain the re-
quired temperature. Information from the load mapping is used to adjust cycle timing to ensure appropriate lethality. System
control must consider the relationship between load position and size relative to temperature control locations.

Biological Indicators

The biological indicator (BI) for dry heat sterilization is Bacillus atrophaeus (ATCC 9372), a thermophilic spore-former with
high resistance to dry heat. The spore challenge is placed on a substrate positioned within the load or on a load item. If spores
are used as intended by the BI manufacturer, the population and resistance information provided by the vendor can be used.
End users should determine the population and resistance of their biological indicator used when inoculating their own items.

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1842 1229.8 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. 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. Thermocouples should be placed into direct contact with the item(s) being
monitored. 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 timetemperature or FH. If the microbial and physical measurements do not correlate,
manufacturers should conduct an investigation and should take corrective action to rectify the discrepancy. This study custom-
arily is performed slightly subminimal to the lower specification limits for time, temperature, and/or cumulative lethality.

ROUTINE PROCESS CONTROL

As with all sterilization processes, after the dry heat sterilization process has been validated, it must be subject to formalized
controls that keep it in a validated state over time. General chapter Sterilization of Compendial Articles 1229 details the general
practices that are appropriate for all sterilization systems. 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, physical measurements, physical integrators and indicators, ongoing process control, change control, pre-
ventive maintenance, and periodic reassessment and training.

REFERENCES
General Chapters

1. USP General ChaptersMicrobiology Expert Committee. An outline of planned changes to USP 1211 Sterilization and
Sterility Assurance of Compendial Articles. Pharm Forum. 2012; 38(2).

1229.9 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 requiredan exception is the validation and monitoring of radiation sterilization with dos-
imetry. The physicochemical indicator provides an immediate visual confirmation that an item has been exposed to a steriliza-
tion process. Performance standards both within and between lots of physicochemical integrators or indicators from a given
manufacturer should be consistent. Integrators or indicators should not interact physically or chemically with any container or
product when placed in the sterilizer load, and should not alter the strength, quality, or purity of the sterilized article. The
integrator or indicator should be positioned such that it does not alter the effectiveness of the sterilization process. The princi-
pal usage of physicochemical integrators and indicators is to provide a rapid means of confirmation of sterilization cycle com-
pletion. This is especially important with single door sterilization chambers where a potential mix-up of nonsterilized and steri-
lized items is more likely. 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 1229.10).

PHYSICOCHEMICAL INTEGRATORS

A physicochemical integrator is defined as a device that responds to one or more sterilization process critical parameters,
which results in a measurable value that can be correlated to microbial lethality. The manufacturers of physicochemical inte-
grators should provide data to demonstrate that the labeled performance characteristics tests of the integrators are met.
Physicochemical integrators require precautions for use and the appropriate interpretive criteria to define their performance
characteristics. Performance of the sterilization apparatus must be ascertained from records generated by calibrated instru-
ments (temperature, pressure, exposure time, gas concentration, and others, as applicable). The integrator can demonstrate
only inadequate or adequate exposure to a combination of sterilization parameters.
Physicochemical integrators for radiation sterilization are designed to react predictably to the delivered radiation dose and
can provide primary evidence of sterilization process effectiveness. The use of dosimeters in radiation sterilization cycle devel-
opment and routine process control is addressed in ANSI/AAMI/ISO 11137-3, Sterilization of health care productsRadia-
tionPart 3: Guidance on dosimetric aspects (1).

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