The Federal Code of Regulations, Part 211 on Good Manufacturing Practices for Finished Pharmaceuticals in section 211.165 states: “There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms.” This statement has been interpreted to mean that an alternate laboratory control test for sterility is required for any batch load of a product that is parametrically released. An appropriate laboratory test for each batch may be a biological indicator, which is included in each batch of product that is terminally sterilized (see Biological Indicators for Sterilization 1035), or a physicochemical indicator or integrator. This requirement may also be met by a primary product release system that includes the documented recording of thermometric measurements systems that are calibrated with a NIST traceability system and that demonstrate a ±0.5 performance capability.

The presence of this chapter in the USP does not mean that chemical indicators and integrators are primary release requirements for parametric released product. The recorded and documented measurements from established thermometric measurement systems and associated process controllers (that have been calibrated and used during initial and periodic validation studies, as well as in routine production) can be considered to be primary, product-release systems for parametric release.

Performance standards within lots and between lots of physicochemical indicators or integrators from a given manufacturer should be consistent. They should not interact physically or chemically with any container or product when placed adjacent to the product for sterilization in the sterilizer load, and should not alter the strength, quality, or purity of the sterilized article. The safety of personnel handling the physicochemical indicators or integrators should also be assessed, and, if need be, appropriate precautions should be taken.

Similar to biological indicators, chemical indicators are considered Class II devices and require the indicator manufacturer to obtain a device 510K approval prior to commercial use.

Recorded process engineering data can be supplemented by the presence in each sterilized batch of a physicochemical indicator. A physicochemical indicator is defined as a device that responds in a measurable fashion to one or more critical sterilization parameters.

A number of different kinds of indicators dependent on chemical or physicochemical means have been developed for monitoring sterilization cycles. Some products are used in a sterilization apparatus for monitoring whether the contents have been exposed to a selected factor (i.e., temperature) of the particular sterilization cycle, but may not show the duration or intensity of such exposure. Chemical and physicochemical indicators are used to monitor a physical parameter of a sterilization apparatus and can be placed on the outside of the packages of articles to be sterilized, or they may be distributed within the sterilizer load. In the latter case, one can evaluate to some extent the effect of the packaging material and configuration of the load on the selected parameter.

A physicochemical integrator is defined as a device that responds to a sterilization process critical parameter, which results in a measurable or quantifiable value that can be correlated to some standard of microbial lethality. Physicochemical integrators have been designed to broadly match the predictable inactivation of those spore preparations in biological indicators that have high and defined resistance to the sterilizing agent.

The manufacturers of physicochemical integrators should provide data to demonstrate that the labeled performance characteristics tests of the integrators are met. Users of physicochemical integrators should verify that specific measured values directly correlate to successful microbial lethality in a validated sterilization cycle.

A physicochemical integrator indicates whether or not the critical combination of physical parameters of a validated sterilization cycle has been met or exceeded. The integrator is not generally used as a substitute for a biological indicator in the development and validation of sterilization cycles. An indication by a physicochemical integrator that the critical combination of physical parameters of a stated sterilization cycle has been achieved should not be considered equivalent to the inactivation of spores of a variety of biological indicators. However, the physicochemical integrator can detect whether the sterilization process has been continued for too long, at too high a temperature or gas concentration, or has been overexposed to radiation.

The interval between the lower range and the upper range of time, or any other designated set of parameters, resembles the survival time and kill time window characteristics of a biological indicator. This interval should not be wider than that desirable for the designated parameter, but may be narrower if the manufacturer is able to achieve consistent performance over a narrower range. Even where a sterilization apparatus with consistent performance is used, cases may occur where the determined performance characteristics of the integrator differ from the label claims. This could represent a difference between the user's apparatus performance and the manufacturer's apparatus used for verifying the label claims. Closer conformity to the label claims may also be shown with any highly developed apparatus, such as a BIER vessel.1,2 Hence, the integrator requires its own precautions in use and has appropriate interpretive criteria within its performance characteristics. Tests for performance characteristics of physicochemical integrators include determination under applicable defined conditions of (a) the maximum time of exposure at which none of the specimens indicates that adequate exposure to the cycle has occurred, and (b) a minimum time of exposure at which all specimens show that adequate exposure to the cycle has occurred. An intermediate time of exposure, where about half the number of specimens show adequate exposure, could indicate an approaching exposure endpoint for the physicochemical integrator.

Because an indicator reflects only the interaction of the physical parameters of sterilization, it will not be affected by some of the factors that may influence the resistance of the microbial load on the products to be sterilized (e.g., progeny resistance, spore population, inoculum substrate, oil, salts, proteins, or residues or configurations), all of which may protect a contaminated area from penetration by the sterilizing agent. (Hence, the inappropriateness of these devices for cycle development.) There are other factors, however, that may affect a biological indicator that could also affect a physicochemical integrator (e.g., interfering configuration of a pack in which the integrator was placed, variations in the applied timing or temperature control, or failure of the apparatus to reach the set temperature or meet other requirements).

Defective performance of the sterilization apparatus generally can be ascertained from gauges and from records of temperature, pressure, time of exposure, and gas concentration, whichever are applicable. The integrator can only indicate inadequate, adequate, or excessive exposure to a combination of critical sterilization parameters. Where an integrator shows inadequate exposure to the sterilization parameters, it is necessary to ascertain whether the gauges and recordings reflect accurately the sterilization conditions within the sterilization chamber. Variations between sterilization vessels, which might affect the efficiency of a selected sterilization cycle, might be detectable by parallel exposure of several integrators in a number of locations in each sterilizer load.

Physicochemical integrators for steam sterilization are designed to react predictably to a particular combination of physical sterilization parameters: temperature, steam pressure, and time of exposure. Deviation to some extent of one or more of these critical parameters, not compensated by modification of other parameters, causes the integrator to indicate failure to reach the preset integrated limits.

Physicochemical integrators for ethylene oxide sterilization are designed with similar general principles as the integrators for steam sterilization, but to react predictably to the particular combination of the physical sterilization parameters: humidity, temperature, sterilizing gas concentration, and time of exposure. Deviation to some extent of one or more of these critical parameters, not compensated by modification of other parameters, causes the integrator to indicate failure to reach the preset integrated limits.

Physicochemical integrators have been designed to match broadly the predictable inactivation of spore preparations that have a high and defined resistance to the sterilizing agent. For steam sterilization, a strain of Bacillus stearothermophilus is used (see Biological Indicator for Steam Sterilization, Paper Carrier), and for ethylene oxide sterilization, a strain of Bacillus subtilis, subspecies niger, is used (see Biological Indicator for Ethylene Oxide Sterilization, Paper Carrier). Since there are no standard preparations of these strains, the performance characteristics of these physicochemical integrators must be interpreted in relation to a specific validated sterilization cycle.

Performance standards within lots and between lots of physicochemical integrators from a given manufacturer should be consistent. The integrators should not interact physically or chemically with container or product when placed adjacent to the product for sterilization in the sterilizer load, and shall not alter the strength, quality, or purity of the sterilized article beyond official requirements. Users should obtain information from integrator manufacturers on whether or not sterilization in the presence of physicochemical integrators may affect particular articles to be sterilized. In addition, safety in using these integrators should be verified.