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USP 39 General Information / á1222ñ Terminally Sterilized Pharmaceutical Products 1613

á1222ñ TERMINALLY STERILIZED PHARMACEUTICAL PRODUCTS—

PARAMETRIC RELEASE

INTRODUCTION

Parametric release is defined as the release of terminally sterilized batches or lots of sterile products based upon compliance
with the defined critical parameters of sterilization without having to perform the requirements under Sterility Tests á71ñ. Para-
metric release is a possibility when the mode of sterilization is very well understood, the physical parameters of processing are
well defined, predictable, and measurable, and the lethality of the cycle has been microbiologically validated through the use
of appropriate biological indicators or, in the case of ionizing radiation, the appropriate microbiological and dosimetric tests.
The use of parametric release for sterilization processes requires prior FDA approval. It should be expected that the regulatory
agencies evaluating submissions including the use of parametric product release would insist upon a well supported scientific
rationale for the sterilization process and well documented validation data. The agencies would need assurance that any mar-
keted sample of product will be sterile and if tested after release would pass the requirements for sterility as found in the gen-
eral chapter Sterility Tests á71ñ.
It is important to consider the limitations of the Sterility Tests á71ñ in the evaluation of terminally sterilized products. The
sterility test described in general chapter á71ñ is limited in its sensitivity and is statistically ill-suited to the evaluation of termi-
nally sterilized products given the exceedingly low probability of contaminated units. Therefore, once a sterilization process is

General Chapters
fully validated and operates consistently, a combination of physical sterilization data such as accumulated lethality or dosimetry
in combination with other methods, such as load monitors (e.g., biological indicators, thermochemical indicators, or physico-
chemical integrators), can provide more accurate information than the sterility test regarding the release of terminally sterilized
product to the marketplace.
There are four modes of sterilization that theoretically and practically could qualify for parametric release: moist heat, dry
heat, ethylene oxide, and ionizing radiation sterilization. This information chapter first will cover the general issues related to
parametric release, regardless of the modes of sterilization, and then discuss some specific modes of sterilization. The chapter
will not address the parametric release of terminally sterilized medical devices.
Terminally sterilized products represent the lowest risk category of sterile pharmaceutical products. Unlike products asepti-
cally manufactured in a microbiologically controlled environment, terminally sterilized products are subjected to a sterilization
process that imparts a measurable minimum sterility assurance level, or SAL. Because aseptic processing relies on exclusion of
microbiological contamination and is not based upon lethality imparted on the product in its sealed container, it is not possi-
ble to estimate the SAL. It is important to note that in the case of aseptic processing, SAL can only be estimated from media fill
contamination rates or other forms of risk assessment. In the case of terminal sterilization, it is possible to calculate a minimum
SAL or Probability of Nonsterility (PNS) quite accurately. Therefore, the term SAL has different contextual meanings when used
to describe aseptic rather than terminal processes, and it is important that this difference is fully understood by scientists and
engineers working in the field of sterile product manufacturing and control. The terms PNS and SAL are often used inter-
changeably.
Terminally sterilized products must have a probability of nonsterility (PNS) of not more than one in a million units produced.
This is often stated as a PNS or SAL of 10–6, or the probability of product bioburden surviving the sterilization process in any
single unit of product is less than one in one million. The proof that a terminally sterilized product complies with the 10–6 PNS
can be accomplished by several different sterilization cycle development approaches. The proper application of these methods
requires extensive scientific knowledge regarding the sterilization method selected for use with a specific product.
The strategies used to validate a terminal sterilization process development fall into three categories:
1. Bioburden-based process.
2. Biological indicator/bioburden combined process.
3. Overkill process.
The bioburden-based process requires extensive knowledge of product bioburden. It should be noted that several radiation
dose-setting procedures involve establishing radiation processes on the basis of bioburden count and radiation resistance. This
method requires that at least a 10–6 PNS be attained for bioburden by the sterilization process. This means that if the product
bioburden action level is 10 microorganisms or one logarithm, at least seven logarithms of bioburden must be inactivated to
assure a 10–6 PNS. The bioburden-based method requires the user to develop suitable critical control points within the process
to control the bioburden titer. Products that readily permit bioburden survival require more controlled manufacturing environ-
ments and more precise in-process control. This process is better suited for cycle development for clean or ultra-clean products
containing a consistently low level of colony forming units (cfu) per product unit with a low frequency of spore-forming micro-
organisms. Also, this process may be necessary to permit terminal sterilization of a product that may potentially lose key quali-
ties or attributes as a result of a more rigorous sterilization process.
The microbiologist may find that formal hazard analysis procedures, such as Hazard Analysis Critical Control Point (HACCP),
are useful in establishing appropriate manufacturing control conditions and in-process control parameters.
The biological indicator/bioburden combined process is generally used when the manufacturer desires a sterilization process
that demonstrates the inactivation of high numbers of biological indicator microorganisms known to be resistant to the proc-

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1614 á1222ñ Terminally Sterilized Pharmaceutical Products / General Information USP 39

ess. While the manufacturer may have preferred utilizing an overkill process, potential loss of some product attributes may oc-
cur in an overkill process thereby necessitating the use of a biological indicator/bioburden combined process. This process re-
quires knowledge of the bioburden load on and in the product, and a database relative to the sterilization resistance of the
bioburden. The relative resistance of the selected biological indicator to that of the bioburden must be established on or in the
product. Frequently, biological indicators bearing approximately 106 spores with D121-value > 1 minute are used in the devel-
opment of such processes. Fractional exposure cycles are generally conducted to determine the relative sterilization resistance
(or D value) between product inoculated with the biological indicator microorganism(s) and frequently encountered biobur-
den. This process is frequently used for sterilization cycle development by manufacturers of terminally sterilized parenteral
products and for ethylene oxide sterilization of medical devices.
The overkill process is frequently used when the article being sterilized is completely inert to the sterilizing agent and steriliza-
tion cycle conditions without any concern for loss of product attributes or quality. When using this process, some bioburden
knowledge should be available to ensure that the materials are not adulterated before sterilization. These data may include
product bioburden count data and knowledge concerning the prevalence of spore formers. The database for this process need
not be as extensive as bioburden data required for the bioburden process or the biological indicator/bioburden process. Gen-
erally, process-resistant biological indicators containing approximately 106 spores are used to establish the effectiveness of the
sterilization process. However, a spore population of N0 can be chosen to confirm adequate process lethality. Overkill is gener-
ally defined as a process that would deliver a minimum of F01 of 12 minutes (see Critical Operating Parameters below) and is
demonstrated biologically based upon the spore log reduction of calibrated biological indicators.

GENERAL REVIEW
General Chapters

Validation of Sterilization Process

Parametric release first requires that the chosen sterilization process be designed and validated to achieve a 10–6 PNS. Valida-
tion of most sterilization processes includes the validation of physical parameters of the process and of its microbiological effec-
tiveness through the use of biological indicators. However, the use of biological indicators for establishing or periodically vali-
dating 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 biologi-
cal 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 microorgan-
isms 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 signifi-
cance 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.

Sterilization Microbiology Control Program

The purpose of this control program is to ensure that the microbiological status of the product, prior to being terminally steri-
lized, 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 evalu-
ate the microbiological status of the environment where the product is processed. The control program is particularly impor-
tant 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 moni-
toring 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 microorgan-
isms, 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 influ-
ence sterilization effectiveness and the determination of sterilization process conditions when using the bioburden or com-
bined bioburden/biological indicator method of cycle development. In the bioburden approach to process development, indi-
cator organisms more resistant than typical bioburden may be used, although extreme differentials in resistance are not re-
quired. Information on the performance of biological indicators may be found in the general chapter Biological Indicators—
Resistance Performance Tests á55ñ.

1 F0 is defined as the calculated equivalent time (in minutes) of process lethality to time at 121.1°, assuming a Z value of 10.0° in the product being sterilized.

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USP 39 General Information / á1222ñ Terminally Sterilized Pharmaceutical Products 1615

Change Control System

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.

Release Procedures

A quality assurance program should be established that describes in detail the batch or lot release steps for parametric re-
lease 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 demon-
strate process control. It is also important to ensure that the sterilizer is current relative to calibration, maintenance, and revali-

General Chapters
dation.
The implementation and practice of parametric release is not an intermittent program. Once such a program is implemen-
ted, release of the sterilized product is made in accordance with the requirements of the regulatory approved program. Prod-
uct release by other means is not acceptable if the predefined critical operational parameters are not achieved.

MODES OF STERILIZATION

Moist Heat Sterilization

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 environ-
ments. Different processes may be used to sterilize products by moist heat, and they include batch-type sterilizers and continu-
ous-type sterilizers.

CRITICAL OPERATING PARAMETERS

A defined list of key process parameters and their respective operating limits are defined and established in the sterilization
process specifications. Critical operating parameters are those that are absolutely essential to ensure product sterilization to a
10–6 PNS. Examples of critical operating parameters may include, but are not limited to, dwell time limits, minimum and maxi-
mum limits for process peak dwell temperature, average peak dwell temperature, and the results of the batch or lot release test
that satisfies the requirements of CFR, Part 211 (e.g., a load monitor results from the laboratory). F0 may be used as a critical
parameter only when temperature and time relationships are well defined. Other measured parameters may be considered
secondary (or noncritical) parameters and may include maximum and minimum time to peak dwell, chamber pressure, and if
applicable, chamber water level, sterilizing water time above defined temperature limits, and recirculating water pump pres-
sure differential.

Ethylene Oxide Sterilization

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

CRITICAL OPERATING PARAMETERS

Critical parameters may include the following: temperature, amount of relative humidity present, ethylene oxide concentra-
tion, overall exposure time, product and load density, and gas permeability factors.
Parametric release of pharmaceutical products can be achieved if an automated measurement system for the critical parame-
ters is employed and sterilization loads are closely defined and validated relative to product types, densities, packaging materi-
als, and overall load configurations. An example of the measurement of critical factors that may be considered for parametric
release would be the use of calibrated ETO pressure recordings to provide an estimate of ETO concentration during the proc-

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1616 á1222ñ Terminally Sterilized Pharmaceutical Products / General Information USP 39

ess hold time or the use of direct measurement of ETO concentration by IR or gas chromatography. Because of variances that
might occur in the key parameters during sterilization, parametric release is not widely used for products sterilized by ETO.
However, to ensure parametric release, in addition to the attainment of process parameters of the ethylene oxide steriliza-
tion, biological indicators (and their sterility testing after sterilization processing) or the use of physicochemical integrators for
the ethylene oxide sterilization are often used as load monitors (critical parameters).

Radiation Sterilization

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 radia-
tion across the density ranges processed in the product carrier. The lowest specified radiation dosage for the process is correla-
ted 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
General Chapters

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 pa-
rameters 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 adjust-
ments 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.

SUMMARY

The conversion to parametric release in lieu of product sterility testing as described in general chapter Sterility Tests á71ñ
requires prior FDA approval. Parametric release is advantageous for terminally sterilized products. The extensiveness of data
required to establish parametric release, compared to the general chapter á71ñ procedures, which lack sensitivity to very low
levels of microbial contamination, can result in a more accurate and reliable assessment of the probability of nonsterility of
product lots.

á1223ñ VALIDATION OF ALTERNATIVE MICROBIOLOGICAL METHODS

INTRODUCTION

This chapter provides guidance on the selection, evaluation, and use of microbiological methods as alternatives to compen-
dial methods. To properly implement alternative methods, one must consider a number of important issues before selecting
the analytical technology and qualifying that method with the actual product. These issues include, but are not limited to,
identification of suitable alternative methodology, development of user specifications for equipment selection, demonstration
of the applicability of the method as a replacement for a standard compendial method, and qualification of the method in the
laboratory.
This chapter outlines:
• User requirements
— Instrument qualification
— Validation of alternate technologies
— Method suitability
• The limitations of the use of CFU as a standard signal for microbiological methods.
• Four novel options for demonstrating equivalence
— Acceptable procedures

2 ANSI/AAMI/ISO 11137-1996, Sterilization of Health Care Products—Requirements for Validation and Routine Control—Radiation Sterilization, July 11, 1994.

Official from May 1, 2016

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