Parametric release first requires that the chosen sterilization process be designed and validated to achieve a 10–6 PNS. Validation of most sterilization processes includes the validation of physical parameters of the process and of its microbiological effectiveness through the use of biological indicators. However, the use of biological indicators for establishing or periodically validating gamma radiation sterilization processes is uncommon. Widely recognized biological indicator organisms are used in the validation of moist heat processes because they provide a means of comparing physically measured lethality data with biological lethality. There should be a reasonable correlation between physically measured lethality data (F0) and biological lethality as determined by the evaluation of the process with biological indicators.

The predictable effectiveness of bioburden-based terminal sterilization is based on the number and resistance of microorganisms on or in a product. For this reason, one component of parametric release is an active microbiology control program to monitor the count and sterilization resistance of product bioburden. Bioburden control and enumeration is of far less significance when the overkill process design is used. In many cases, overkill processes do not require extensive ongoing assessment of bioburden and require less in-process control of the manufacturing environment.

The purpose of this control program is to ensure that the microbiological status of the product, prior to being terminally sterilized, has not significantly deviated from the established microbiological control level used for validation of the sterilization process. The microbiology control program includes the monitoring of the bioburden on or in the product and the monitoring of the microbiological status of any necessary containers, closures, or packaging materials. Also included is a program to evaluate the microbiological status of the environment where the product is processed. The control program is particularly important in cases where the terminal sterilization is not based on overkill, but rather on the bioburden or combined bioburden/biological indicator cycle development approach. In many cases, bioburden control and manufacturing environmental monitoring will not be required for overkill process designs, where the F0 of the process is at least 12 minutes. In other cases, even when overkill processes are employed, some limited monitoring will be needed. Monitoring of overkill processes for bioburden is generally limited to those products that support microbial growth. Of particular concern in this case is the potential for the product to be contaminated with microbial toxins or to be degraded by microorganisms.

The frequency of monitoring will depend on the variations of bioburden from potential sources. The number of microorganisms, their identification, as well as their resistance to the specified sterilization mode should be considered when parametric release of terminally sterilized product is established. Resistance to a specified sterilization mode by different species can influence sterilization effectiveness and the determination of sterilization process conditions when using the bioburden or combined bioburden/biological indicator method of cycle development. In the bioburden approach to process development, indicator organisms more resistant than typical bioburden may be used, although extreme differentials in resistance are not required. Information on the performance of biological indicators may be found in the general chapter Biological Indicators—Resistance Performance Tests 55.

Changes introduced to the sterilization processing equipment could result in a significant departure of the initially validated parametric release process. It is, therefore, essential that a change control system be instituted. A change control system is a formal system with appropriate standard operating procedures, which would include approval of changes in the sterilization processing equipment. This system would assess all the changes in relation to the critical parameters included in parametric release. The change control system also includes technical and management review and criteria for acceptance or revision of changes. If a change would significantly affect any critical parameter, each parameter would have to be revalidated in terms of sterility assurance of the pharmaceutical product to a minimum 10–6 PNS. Appropriate regulatory notification would also be part of the revalidation process.

A quality assurance program should be established that describes in detail the batch or lot release steps for parametric release of sterilized products and the required documentation. Although the assessment of the sterility assurance of products is primarily based on measurement of physical process parameters, a number of areas should be reviewed, documented, and approved for the parametric release of these products. These areas may include the following: a review of batch records; a review of the ongoing microbiological environmental control program results and presterilization bioburden; and a review of records of thermographic data, load monitors, and results of critical and noncritical data that may have been used to demonstrate process control. It is also important to ensure that the sterilizer is current relative to calibration, maintenance, and revalidation.

The implementation and practice of parametric release is not an intermittent program. Once such a program is implemented, release of the sterilized product is made in accordance with the requirements of the regulatory approved program. Product release by other means is not acceptable if the predefined critical operational parameters are not achieved.

Moist heat sterilization of pharmaceutical products includes several types of sterilizing environments and sterilizing media. Saturated steam, hot water spray, and submerged hot water processes are all considered as moist heat sterilizing environments. Different processes may be used to sterilize products by moist heat, and they include batch-type sterilizers and continuous-type sterilizers.

The application of parametric release of pharmaceutical products sterilized by ethylene oxide is more difficult than parametric release of products sterilized by moist heat processes. Critical parameters for ethylene oxide (ETO) sterilization are interrelated and more complex than moist heat processes.

Two radiation sterilizing processes have been used: gamma and electron beam sterilization (i.e., ionizing radiation). Some pharmaceutical products, either in bulk or in their finished formats, have been sterilized by radiation. In discussing the critical parameters of radiation sterilization necessary for parametric release, it is customary to refer to parametric release as dosimetric release. Dosimetric release is provided by the use of a chemical dosimeter that measures the delivery of a minimum specified radiation dosage, which has been shown to provide sterilization of the product to a minimum 10–6 PNS.

The use of a dosimeter in ionizing radiation sterilization measures delivery of a minimum absorbed radiation dose to a pre-established low dose zone in the irradiated product carrier. This will require mapping of the profile of absorbed ionizing radiation across the density ranges processed in the product carrier. The lowest specified radiation dosage for the process is correlated to predictable bioburden reduction levels by any one of the three documented methods.2 An alternative method may be considered whereby extensive product bioburden count and radiation resistance data are available. Dose verification studies would be conducted to ensure that the worst case bioburden load, relative to resistance and numbers, can be inactivated at the lowest dose zone in the carrier system to provide at least a 10–6 PNS. This method would of course require an ongoing program of bioburden assessment. The target for the radiation cycle is a minimum 10–6 PNS relative to the product bioburden. Dosimetric release of a radiation-sterilized product depends on the delivery of at least a minimum dosage; thus, the critical operational parameters that govern the delivery of that dosage must be within specified limits. These operational critical parameters may include the following: a stacking configuration within the radiation carrier, bulk density of the product, speed of the conveyor or carrier system, distance to the radiation source, duration of product exposure, and appropriate defined adjustments for a decaying radiation source. Demonstration of consistency in the absorbed radiation dosage at areas of minimum and maximum zones of radiation absorption within the fully loaded carriers on a batch-to-batch basis is a necessary condition for dosimetric release of radiation-sterilized pharmaceutical products.