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First Supplement to USP 39NF 34 General Information / 1229.12 New Sterilization Methods 7819

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).


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).


A physicochemical indicator is defined as a device that provides visual evidence of exposure to one or more critical steriliza-
tion parameters. Physicochemical indicators cannot provide primary evidence of sterilization efficacy.


1. ANSI/AAMI/ISO 11137-3:2006/(R)2010, Sterilization of health care productsRadiationPart 3: guidance on dosimetric

aspects. New York: American National Standards Institute; 2010.
1S (USP39)

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Sterilization processes are developed for the elimination of viable microorganisms while preserving the essential physical,
chemical, and biological properties of the materials subjected to them. Where this cannot be accomplished by the sterilization
methods described in Sterilization of Compendial Articles 1229, it may be possible to sterilize by using a proposed method not
commonly used. When doing so, it is the end user's responsibility to demonstrate that the proposed new method can be used
safely and effectively.


The major steps in the implementation of a new sterilization method include the following:
Elimination of any established method through experimental evidence and/or comprehensive literature review of any ma-
terials used
A literature review to identify supportive information on the proposed method
Identification and confirmation of reproducible lethality against a broad range of microorganisms, including bacterial
Identification and definition of critical process parameters necessary to ensure sufficient lethality. The effective range of
these parameters should be explored to identify necessary conditions for the proposed sterilization process. Among the
parameters to be considered, depending upon the nature of the process under consideration, are process dwell time,
temperature, concentration, energy or power, and relative humidity. This evaluation should include positive and negative
controls to ensure that the proposed method is in fact responsible for microbial destruction.

Official from December 1, 2016

Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.
Accessed from by mvpstn3kts on Thu Apr 06 04:44:27 EDT 2017
7820 1229.12 New Sterilization Methods / General Information First Supplement to USP 39NF 34

The selection of a biological indicator (usually a spore-forming microorganism) with increased resistance to the steriliza-
tion method
Evaluation of the proposed method against anticipated bioburden microorganisms and comparison of relative resistance
of the bioburden microorganism to that of the chosen biological indicator
The identification of in-process and/or post-process measurements and/or analysis that can reliably confirm the effective-
ness of the proposed sterilization process.
Where the proposed new method is used for materials intended for human and/or veterinary use, the relevant regulatory
authorities should be contacted to secure their acceptance before either investigational or clinical usage. Validation of the pro-
posed new method should be completed before use on a commercial basis. 1S (USP39)

Official from December 1, 2016

Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.
Accessed from by mvpstn3kts on Thu Apr 06 04:44:27 EDT 2017
First Supplement to USP 39NF 34 Dietary Supplements / 2251 Adulteration of Dietary Supplements 7821

Dietary Supplements
General Chapters Information
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The illegal addition of undeclared synthetic compounds to products marketed as dietary supplements1 (DS) is a serious prob-
lem. This fraud is practiced to impart therapeutic effects that cannot be achieved by the supplement constituents alone. In-
creasingly, synthetic intermediates and structural analogs of the pharmaceuticals and drugs that have been discontinued or
withdrawn from the market due to unsatisfactory safety profiles are being used as adulterants. Multiple adulterating com-
pounds may be added to a single DS, frequently in erratic amounts.
The proposed test methodologies facilitate screening of DS for synthetic adulterants. No individual technique is capable of ad-
dressing all potential analytes; thus, a combination of orthogonal approaches adds certainty to the analytical outcome. Mass
spectrometric techniques provide strong substantiation of the analytical findings. In some cases, e.g., with hormonal drugs,
the amounts of physiologically relevant adulterants may be so low that GC-MS or LC-MS may be the only fitting analytical
The express purpose of assembling the procedures recommended herein is their utility in DS screening. The level of evidence
achievable by application of one or several of the recommended procedures is ultimately dictated by the specific require-
ments of the end-user. It should be noted that structure elucidation and quantitative assessment of adulterants are beyond
the scope of this chapter.
This chapter is meant to be updated regularly, thereby counteracting the efforts of adulterators, as novel analogs are being
developed, new concealment methodologies for the adulterants are introduced, or improvements to the methods of analy-
sis are realized.
The following major categories of adulterated DS are recognized:
Sexual Enhancement: This category is also referred to as the Erectile Dysfunction (ED) category. It encompasses a func-
tionally coherent group of adulterants, including several approved drugs, their numerous approved and unapproved
analogs, synthetic intermediates, and derivatives. Their functionality is manifested by inhibition of phosphodiesterase
type 5 enzyme (PDE5), which hydrolyzes cyclic guanosine 3,5-monophosphate (cGMP); this group of drugs is frequent-
ly identified as PDE5 inhibitors. Screening methods for DS adulterated with ED drugs are presented in Appendix A.
Weight Loss (WL): This category comprises a functionally and chemically diverse collection of compounds that include
stimulants, laxatives, diuretics, anorexiants, and psychoactive drugs. Although stimulants constitute an important seg-
ment of WL adulterants, the oral anorexiant sibutramine dominates this category, frequently in combination with phe-
nolphthalein, a laxative. Methods for analysis of DS adulterated with WL drugs will be addressed in Appendix B (to
Sports Performance Enhancement (SPE): These compounds constitute the third major category of adulteration. Pro-
fessional and amateur athletes are targeted with designer anabolic steroids and stimulants, which are systematically
banned by the World Anti-Doping Agency. Functional and structural diversity, synthetic proclivity of the adulterators,
and the generally small amounts of the infringing substances required to elicit a therapeutic effect make this category
especially challenging to address. These supplements are customarily formulated in protein- and fat-rich matrices,

1 In the United States, dietary supplements are defined as substances that are ingested, in agreement with 21 U.S.Code 321(ff)(2)(A)(i). Definitions of dietary

supplements, nutritional supplements, functional foods, and bioactive food additives may vary extensively, depending on local or national legislation. In the mar-
ketplace, there is a trend toward expanding the mode of delivery of the adulterating compounds to routes not covered by the regulatory definition for dietary
supplements, i.e., topical oils, creams, lotions, e-cigarettes, chewing gums, sprays, and others. Such novel delivery systems present unique challenges, particularly
from the standpoint of sample preparation, and are not considered for the purposes of this chapter to be dietary supplements. However, recognizing the emerging
threat, USP chooses to highlight the existence of these products. In no way should mention of these products be interpreted as a comment on their legal status or
be perceived as an expansion of the definition of DS.

Official from December 1, 2016

Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.