Guidance for Industry and FDA Reviewers
Content and Format of Premarket
Notification [510(k)] Submissions for
Liquid Chemical Sterilants/
High Level Disinfectants
Document issued on:  January 3, 2000
This document supersedes Guidance on the Content and Format of Premarket Notification [510(k)]
Submissions for Liquid Chemical Sterilants and High Level Disinfectants, December 18, 1997
U.S. Department Of Health And Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Infection Control Devices Branch
Division of Dental, Infection Control and General Hospital Devices
Office of Device Evaluation Preface
Public Comment
Comments and suggestions may be submitted at any time for Agency consideration to Chiu S. Lin,
Ph.D., CDRH, HFZ-480, 9200 Corporate Boulevard, Rockville, MD 20850.  Comments may
not be acted upon by the Agency until the document is next revised or updated.  For questions
regarding the use or interpretation of this guidance contact Chiu S. Lin, Ph.D. at (301) 443-8913 
or by electronic mail at cxl@cdrh.fda.gov.
Additional Copies
World Wide Web/CDRH home page: http://www.fda.gov/cdrh/ode/397.pdf, or CDRH Facts on
Demand at 1-800-899-0381 or 301-827-0111, specify number 397 when prompted for the
document shelf number.
2 Content and Format of Premarket
Notification [510(k)] Submissions for Liquid
1
Chemical Sterilants/High Level Disinfectants
BACKGROUND
This guidance was developed by the Infection Control Devices Branch, Division of Dental, Infection
Control and General Hospital Devices, Office of Device Evaluation (ODE), Center for Devices and
Radiological Health (CDRH), Food and Drug Administration (FDA).
The FDA regulates the introduction of medical devices into interstate commerce.  A person intending
to market a liquid chemical sterilant/high level disinfectant for use on reusable heat sensitive critical
and semicritical medical devices must submit a premarket notification [510(k)] submission to the FDA
prior to its introduction into interstate commerce. Regulations governing the general content and
format of 510(k) submissions are codified under 21 Code of Federal Regulations, Part 807.  These
and other regulatory requirements pertaining to the marketing of a new medical device are discussed
in guidance documents available from the CDRH Division of Small Manufacturers Assistance (DSMA).
 This guidance document provides 510(k) applicants with specific recommendations regarding
information and data to be submitted to the FDA in a 510(k) submission for liquid chemical
sterilants/high level disinfectants.
The effective use of liquid chemical sterilants/high level disinfectants is important in preventing
nosocomial infections.  The use of comprehensive, scientifically sound criteria for the evaluation of
liquid chemical sterilants/high level disinfectants is essential to help ensure that these agents are safe
and effective for their intended use.  The FDA recognizes the importance of providing applicants and
other interested parties with the agency's 510(k) submission criteria for liquid chemical sterilants/high
level disinfectants.  This document facilitates the assembly of necessary data, maintains consistency
of reviews, and provides for a more efficient regulatory process.
This guidance is predicated upon the legal principles of the 510(k) process.  It also draws upon the
long-standing regulatory and scientific basis for evaluation of germicides by other federal agencies. It
is a product of interactions with interested parties in industry, government, and academia as well as
with infection control and other health care professionals. 
The Food Quality Protection Act of 1996 (FQPA) exempted liquid chemical sterilants (and the
subordinate high level disinfectants) intended for use to process reusable critical and semicritical
medical devices from the definition of a pesticide under the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA). 
______________________________________
1This document is intended to provide guidance.  It represents the Agencys current thinking on the above.   It does not
create or confer any rights for or on any person and does not operate to bind FDA or the public.  An alternative
approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.
3 The Environmental Protection Agency (EPA) no longer regulates such sterilants/high level
disinfectants.  The FDA now has sole regulatory jurisdiction over liquid chemical sterilants/high level
disinfectants intended for use to process reusable heat sensitive critical and semicritical medical
devices.  For this reason, this document pertains only to liquid chemical sterilants/high level
disinfectants used to process reusable heat sensitive critical and semicritical medical devices. This
guidance document incorporates the provisions of the FQPA and the agreements between the FDA
and the EPA.
The FDA incorporated comments on the content of this document, which were submitted to the FDA
by industry, into this final document.  This final document replaces FDAs 1992 guidance document,
Guidance on the Content and Format of Premarket Notification [510(k)] Submissions for Liquid
Chemical Germicides, dated January 31, 1992 and other versions of the draft guidance document. 
Method development, research and discussions about the germicide evaluation process are ongoing.
 Therefore, this document is not static and will be revised periodically so that it remains current with
state of the art developments in the field of infection control.
4 TABLE OF CONTENTS
Page
I.  INTRODUCTION  7
I.A.  Scope 7
I.B.  Exclusions 7
I.C.  Definitions 7
I.D.  Regulatory Authority and Classification of Liquid Chemical Sterilants/HLD 10
I.E.  Device Modifications 11
I.F.  The 510(k) Paradigm: Alternate Approaches to Demonstrating Substantial Equivalence 12
 
II.   GENERAL PRINCIPLES REGARDING PRESENTATION DATA  13
II.A   Editorial Considerations 13
II.B.  Abbreviations 13
II.C.  Data Availability 13
II.D.  Tables and Graphs 13
II.E.  Published Literature 13
II.F.  Protocols and Data Analysis  13
II.G.  Submitting a 510(k) 14
II.H.  Responding to a FDA Request for Additional Information 14
 
III.   FORMAT AND CONTENT  16
III.A. Cover Letter and Introductory Information 16
III.B. Table of Contents 16
III.C. Information Required by the Safe Medical Devices Act of 1990 16
III.D. Comparison of the New Germicide to the Predicate Germicide 17
III.E. Authorization for Data Access 17
III.F. Physical and Chemical Properties 17
III.G. Labeling  21
III.H. Efficacy Data  28
III.I   Biocompatibility  37
III.J. Device and Material Compatibility Qualification                                                                     39
III.K. Chemical Indicators for Liquid Chemical Germicides  41
IV.  CONTACTS AND ADDRESSES                                                                                                  45
 
V.  510(k) CHECKLIST  46
 
VI.  APPENDIX A  Special 510(k)  47
VII.  APPENDIX B  Abbreviated 510(k)  49
VIII.   APPENDIX C  Truth and Accurate Statement             50
IX.    APPENDIX D  510(k) Statement  51
X.     APPENDIX E  Indications for Use Statement  52
XI.  APPENDIX F  Declaration of Conformity with Design Controls             53
5 XII.  APPENDIX G  Declaration of Conformance with Consensus Standards             54
XIII.  APPENDIX H  Example of EPA Confidential Statement of Formula  55
XIV.  REFERENCES  57
6 I.  INTRODUCTION
I.A.   Scope
This document provides guidance concerning the content and format of 510(k) submissions for liquid
chemical sterilants/high level disinfectants intended for the sterilization and/or high level disinfection of
reusable heat sensitive critical and semicritical medical devices. 
The Food and Drug Administration (FDA) encourages a sponsor to meet with FDA representatives
prior to submitting a 510(k) for a liquid chemical sterilant/high level disinfectant to discuss germicide-
specific protocols and preliminary data.
I.B.   Exclusions
This document EXCLUDES the following products:
 
1.  an antimicrobial agent, such as ethylene oxide, that is a gas or chemical vapor at the time of use;
these agents are used with sterilizing systems and are addressed in a separate guidance
document (see Guidance on Premarket Notification [510(k)] Submissions for Sterilizers Intended
for Use in Health Care Facilities).
 
2.  chemical germicide technology used only in a manufacturing setting
 
3.  chemical germicides intended to disinfect contact lenses and hemodialyzers (A guidance
document for germicides used for reprocessing hemodialyzers is in preparation.)
 
4.  antimicrobials that are indicated for use on the body (antiseptics)
 
5.  general purpose disinfectants per the definition set forth in the June 4, 1993 Memorandum
of Understanding (MOU) between the FDA and the Environmental Protection Agency
(EPA); The MOU is included as an attachment to the October 1993 draft document,
Guidance on the Content and Format of Premarket Notification [510(k)] Submissions for
General Purpose Disinfectants, which is available from the FDAs Division of Small
Manufacturers Assistance (DSMA, 1-800-538-2041).
 
 I.C.   Definitions
 
1.  Bioburden (microbial load): Population of viable microorganisms on a raw material, component, a
finished product and/or a package (ANSI/AAMI/ISO 11134-1993); also known as bioload or
microbial load.
2.  Chemical indicator for a liquid chemical germicide:  A monitoring device designed to respond with
a characteristic chemical reaction to the concentration of the active ingredient(s).  Chemical
indicators are intended to indicate a visible change (pass response) to the user when the
minimum set concentration is present.  Chemical indicators for liquid chemical germicides do not
reflect other critical parameters, such as contact time and temperature, required to achieve
sterilization or disinfection.
 
3.  Cleaning (or precleaning): The removal, usually with detergent and water, of adherent visible soil,
blood, protein substances, and other debris from the surfaces, crevices, serrations, joints, and
lumens of instruments, devices, and equipment by a manual or mechanical process that prepares
7 the items for safe handling and/or further decontamination (AAMI, 1995).
 
4.  Death Rate Curve (or Survivor Curve): The graphic representation of the microbial death rate
kinetics for a specific microbicidal agent on a defined microbial population (AAMI, 1995).
 
5.  Decontamination: Disinfection or sterilization of infected articles to make them suitable for use
(Block, 1991).
6.  Disinfectant: An agent that destroys pathogenic and other kinds of microorganisms by chemical
or physical means.  A disinfectant destroys most recognized pathogenic microorganisms, but not
necessarily all microbial forms, such as bacterial spores.
 
7.  Disinfection:  The destruction of pathogenic and other kinds of microorganisms by physical or
chemical means.  Disinfection is a less lethal process than sterilization, since it destroys most
recognized pathogenic microorganisms, but not necessarily all microbial forms, such as bacterial
spores.  Disinfection processes do not ensure the margin of safety associated with sterilization
processes (AAMI, 1995).
 
8.  Germicide: An agent that destroys microorganisms, especially pathogenic organisms.  Other
terms with the suffix -cide (e.g., virucide, fungicide, bactericide, sporicide, tuberculocide) destroy
the microorganism identified by the prefix (Block, 1991).
 
9.  High Level Disinfectant:  A germicide that inactivates all microbial pathogens, except large
numbers of bacterial endospores, when used according to labeling (Rutala, 1990; Spaulding,
1970).  The FDA further defines a high level disinfectant as a sterilant used under the same
contact conditions except for a shorter contact time.
 
10.  Inorganic and Organic Load: The naturally occurring or artificially placed inorganic (e.g., metal
salts) or organic (e.g., proteins) contaminants present on a medical device prior to exposure to a
microbicidal process. 
 
11. Medical Device (as defined by the Food, Drug, and Cosmetic Act): An instrument, apparatus,
implement, machine, contrivance, implant, in vitro reagent, or other similar or related article,
including any component, part, or accessory, which is (1) recognized in the official National
Formulary, or the United States Pharmacopeia, or any supplement to them, (2) intended for use in
the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of
disease, in man or animals, or (3) intended to affect the structure or any function of the body of
man or other animals, and which does not achieve its primary intended purposes through chemical
action within or on the body of man or other animals and which is not dependent upon being
metabolized for the achievement of any of its principal intended purposes.
12.  Minimum Effective Concentration (MEC): The minimum concentration of a liquid chemical
germicide, which achieves the claimed microbicidal activity.  The MEC is determined by dose
response testing.
13.  Minimum Recommended Concentration (MRC):  The minimum concentration of a liquid chemical
germicide at which efficacy has been demonstrated.  The MRC is not necessarily an MEC as
determined by dose response testing.
14.  Process Residue: The substance remaining on a medical device after exposure to a
decontamination, disinfection, or terminal sterilization process.
 
8 15.  Spore (or endospore): The dormant state of an organism, typically a bacterium or fungus which
exhibits a lack of biosynthetic activity, reduced respiratory activity, and has resistance to heat,
radiation, desiccation and various chemical agents.
 
16.  Sterilant:  An agent that destroys all viable forms of microbial life.
 
17.  Sterile:  State of being free from viable microorganisms (ANSI/AAMI/ISO 11134-1993).
 
18.  Sterility Assurance Level (SAL):  The probability of survival of microorganisms after a terminal
sterilization process, and a predictor of the efficacy of the process (AAMI, 1995).
 
19.  Sterilization: Validated process used to render a product free of all forms of viable
microorganisms (ANSI/AAMI/ISO 11134-1993).
 
20.  Total kill endpoint analysis:  Testing conducted at points below and above the established end
point to confirm the germicidal contact time end point. 
 
21.  Unit: A specified substrate or carrier upon which a specified number of test organisms are
inoculated.  A unit may be a specified volume, weight, or surface area.  For example, a unit could
be specified as a test tube or Petri plate, an entire device, a component of a device (if the device
must be disassembled prior to sterilization or disinfection), or a portion of a device.
 
22.  Verification:  Confirmation by examination and provision of objective evidence that specified
requirements have been fulfilled (Section 820.3 of the FDA Quality System Regulation 1996).
 
23.  Vegetative State: An active growth phase of an organism.
9 I.D.   Regulatory Authority and Classification of Liquid Chemical Germicides
The FDA regulates medical devices under authority of the Federal Food, Drug, and Cosmetic Act
(FD&C Act).  The FDA classified medical devices that were in commercial distribution prior to the 1976
amendments to the FD&C Act for medical devices, or the so-called pre-amendments devices, into one
of three regulatory classes: Class I, II, or III.  The class establishes the regulatory controls that are
necessary to provide reasonable assurance of the device safety and effectiveness.  Class I devices
are subject to general controls.  Class II devices are subject to general controls and any FDA-
established special controls (as amended by the Safe Medical Devices Act of 1990).  Class III devices
are subject to premarket approval procedures. Call the FDA's Division of Small Manufacturers
Assistance (DSMA) at 1-800-538-2041 for guidance on general controls.
When the FDA classified the general hospital and personal use devices (45 FR 69678-69737,
October 21, 1980), liquid chemical germicides were not included.  At that time, the FDA regulated only
those liquid chemical germicides with labeled indications for use on specific devices (e.g.,
hemodialyzers).  Because the FDA considered liquid chemical germicides to be accessories to the
devices they were used to process, the FDA regulated them in the same class as the primary device. 
Thus, the same liquid chemical germicide could be regulated as a Class I, Class II, and Class III
device. 
In the early 1990s, the FDA began actively regulating all liquid chemical germicides with health care
indications.  In order to avoid the potential problem of regulating the same product under multiple
classes, the FDA decided to regulate liquid chemical germicides as a separate type of medical device
and determined that these were unclassified devices.  Additionally, the FDA adapted the terminology
and classification scheme described by Spaulding (1970) for devices (i.e., critical, semicritical and
noncritical) and the four levels of processing as proposed by the Centers for Disease Control and
Prevention (CDC), sterilization, high level disinfection, intermediate level disinfection, and low level
disinfection (Favero and Bond, 1993), to categorize medical devices.
Furthermore, the FDA developed criteria to support efficacy claims for the processing levels.  The
FDA defines a high level disinfectant as a germicide that demonstrates efficacy as a sterilant per
results of the Association of Official Analytical Chemists (AOAC) Official Methods 966.04 Sporicidal
Activity of Disinfectants (AOAC Sporicidal Test) at a longer contact time than that needed for high
level disinfection.  (This document discusses these criteria in greater detail later in Section III.H.) 
Therefore, the FDA defined three types of liquid chemical germicides for processing medical devices:
sterilant/high level disinfectant, intermediate level disinfectant, and low level disinfectant.  From a
regulatory perspective, the FDA divided these products into two categories: 
(1)  liquid chemical sterilants/high level disinfectants for processing critical and semicritical
devices
(2)  general purpose disinfectants that include intermediate level disinfectants and low level
disinfectants for processing noncritical devices and medical equipment surfaces
The EPA regulates liquid chemical germicides as pesticides under the Federal Insecticide, Fungicide,
and Rodenticide Act (FIFRA).  In an effort to ease the burden of this dual regulation, the FDA and the
EPA signed a Memorandum of Understanding (MOU) (FDA, 1993; FDA, 1994) which gave the FDA
primary responsibility for premarket efficacy and safety data review of liquid chemical sterilants/high
level disinfectants and the EPA primary responsibility for premarket efficacy and safety data review of
general purpose disinfectants. The MOU also provided interim procedures to eliminate dual efficacy
and safety data reviews until completion of the EPA rulemaking process to exempt liquid chemical
10 sterilants/high level disinfectants from regulation under FIFRA and the FDA classification process to
exempt general purpose disinfectants from 510(k) requirements.
In 1996, the Food Quality Protection Act (FQPA) exempted liquid chemical sterilants/high level
disinfectants used to process critical and semicritical medical devices from the definition of a pesticide
under FIFRA and no longer regulates them.  The FDA now has sole regulatory jurisdiction over liquid
chemical sterilants/high level disinfectants used to process reusable critical and semicritical medical
devices.  The FQPA did not affect the regulatory authority over general purpose disinfectants;
therefore, the MOU remains in effect for these products and the dual regulatory requirements
continue until the FDA classifies and exempts them from 510(k) requirements.
In an effort to complete the classification rulemaking process, the FDA convened the General Hospital
and Personal Use Devices Panel (Panel) in July 1995 to classify liquid chemical sterilants/high level
disinfectants and general purpose disinfectants. The FDA Panel recommended that liquid chemical
sterilants/high level disinfectants be classified as Class II devices (general and special controls) and
that general purpose disinfectants be classified as Class I devices (general controls) and be exempted
from 510(k) requirements.  The FDA accepted the Panels recommendation and published this
classification plan as a proposed rule in the Federal Register on November 6, 1998 (Volume 63,
Number 215, pages 59917-59921).  When the FDA publishes the final classification rule, the rule will
exempt the general purpose disinfectants from the FDA 510(k) requirements. The FDA currently
regulates liquid chemical sterilants/high level disinfectants in the same manner as Class II devices;
therefore, this final classification rule will only codify the current regulatory process.
This guidance document pertains only to liquid chemical sterilants/high level disinfectants used to
process reusable critical and semicritical medical devices, an replaces the 1992 guidance document
for liquid chemical germicides.  The October 1993 draft document, "Guidance on the Content and
Format of Premarket Notification [510(K)] Submissions for General Purpose Disinfectants" is available
to provide specific guidance for a 510(k) submission of general purpose disinfectants until they are
exempted. 
I.E.  Device Modifications
21 CFR 807.81 specifies that a premarket notification submission is required when significant
modifications are made to a 510(k) cleared device.  Persons intending to market a modified medical
device should refer to the FDA document entitled, Deciding When to Submit a 510(k) for a Change to
an Existing Device (www.fda.gov/cdrh/ode/510kmod.pdf or www.fda.gov/cdrh/ode/510kmod.pdfl).
The following modifications are examples of changes that may be made to 510(k) cleared liquid
chemical sterilants/high level disinfectants but do not require a new 510(k) submission:
1.  changes in containers/closures based on data from the FDA accepted stability protocols in the
original 510(k)
2.  additions to lists of compatible materials in labeling based on data from the FDA accepted test
regimen described in the original 510(k)
3.  changes to cleared directions for use that only clarify the directions
4.  addition of new precautions, warnings, contraindications, or adverse effects
5.  reduction in (or narrowing of) tolerances for ingredient specifications
11 6.  changes in source of raw materials
7.  extensions of expiration date based on data from the FDA accepted protocols in the original
510(k)
Note:  Under 21 CFR 807.85(b) a distributor of a specific germicide who markets the germicide under
its own name and a repackager who places its own name on a germicide and does not change any
other labeling or otherwise affect the device (e.g., change specifications or formulation) shall be
exempt from 510(k) requirements if a premarket notification has been submitted for the specific
germicide and previously found substantially equivalent, or the germicide is a pre-1976 germicide.
I.F.  The 510(k) Paradigm: Alternate Approaches to Demonstrating Substantial Equivalence
Section 510(k) of the FD&C Act requires a person who intends to introduce a device into commercial
distribution to submit a premarket notification, or 510(k), to the FDA at least 90 days before
commercial distribution is to begin.  Section 513(i) of the Act stipulates that the FDA may issue an
order of substantial equivalence, only upon making a determination that the device to be introduced
into commercial distribution is as safe and effective as a legally marketed device.  In the document, A
New 510(k) Paradigm, (http://www.fda.gov/cdrh/ode/parad510.html) the FDA describes alternative
approaches to the traditional method of demonstrating substantial equivalence.  These alternative
approaches are within the existing statutory framework, and it is anticipated that they will conserve the
Agencys review resources while facilitating the introduction of safe and effective devices into
interstate commerce.  The first alternative, the Special 510(k): Device Modification, utilizes certain
aspects of the Quality System Regulation, while the second alternative, the Abbreviated 510(k),
relies on the use of special controls and consensus standards to facilitate 510(k) review.  See
Appendices A and B for outlines of information to include in a Special 510(k) and Abbreviated 510(k),
respectively.
12 II.  GENERAL PRINCIPLES REGARDING PRESENTATION OF DATA
A well written and organized submission facilitates the review process.  The FDA recommends that the
sponsor incorporate the following principles during preparation of their application.
II.A.  Editorial Considerations
1.  Carefully edit and scientifically review the 510(k) submission.
2.  Proofread the document to assure that all pages are properly indicated, consecutive, distinctly
copied, and readable.
II.B.  Abbreviations
1.  Use standard abbreviations acceptable to a peer reviewed journal wherever possible. 
2.  Identify all abbreviations at the beginning of each section in which they are used or in footnotes
to tables and graphs.
II.C.  Data Availability
1.  Retain data gathered during preparation of the 510(k) submission in a controlled and well-
organized format so that it is readily available.  Additional information or analysis is sometimes
necessary for completing a review. 
2.  Bring errors to the FDA's attention immediately.
II.D.  Tables and Graphs
1.  Prepare tables and graphs of a quality acceptable to a peer reviewed scientific journal.
2.  Identify each table and graph with a title that clearly identifies the nature of the data.
3.  Explain all symbols with a footnote or reference page.
4.  Provide data tables for interpretation when graphs are presented. 
II.E.  Published Literature
1.  Summarize all referenced reports and data and explain how this information relates to the 510(k)
submission.
2.  Facilitate the review process by including references for published methods or data cited in
submissions and reprints of other published reports or data. 
II.F.  Protocols and Data Analysis
1.  Provide the actual test reports that include the protocol (objectives, precise description of
materials, experimental methods, controls), observations and statistical analyses, and the
conclusions and comments on the test results.  This guidance document addresses additional
13 specific directions on protocols in subsequent sections.
 
2.  Clearly describe analytical methods and utilize recognized analytical and statistical methods.  For
statistical equivalence, please refer to Blackwelder (1982, 1995).
 
3.  In each study report, specify if the study is in accordance with good laboratory practices (GLP)
regulations (21 CFR Part 58) and explain any deviations.
II.G.  Submitting a 510(k)
1.  Submit a single 510(k) submission for a common product group, (e.g., same active ingredients
and claims but different size containers).  Other differences may require submission as separate
510(k)s and are considered on a case by case basis.
2.  Include a response to all elements in Part III below or include an explanation for why data or
information is not supplied, or for why the alternative information provided is sufficient.  If after a
cursory review, the FDA finds a 510(k) submission grossly incomplete, the FDA will refuse to
accept the document and immediately delete it and then notify the applicant.
II.H.  Responding to a FDA Request for Additional Information
Under 21 CFR Section 807.87(l), a 510(k) sponsor may amend their document to include additional
information requested by the FDA that is necessary to reach a finding as to whether the device is
substantially equivalent to a legally marketed device.  The FDA may notify the sponsor by telephone
and/or in writing of any additional information needed during the review.  The FDA typically telephones
sponsors to clarify minor deficiencies. Once the FDA notifies the applicant of deficiencies, the FDA
places the 510(k) on hold. The FDA considers additional information submitted in response to an FDA
request to be a supplement to the 510(k).  The FDA encourages the sponsor to contact the FDA
reviewer in the Infection Control Devices Branch before responding to deficiency letters to clarify or
discuss the deficiencies.
1.  Within 30 days of the request for additional information, elect to do one of the following:
a.  provide the requested additional information in writing to the Document Mail Center
 
b.  formally withdraw the 510(k) submission in writing to the Document Mail Center
 
c.  allow the submission to be deleted from the system by the FDA by not responding
 
2.  Request limited extensions of the 30-day response period by submitting a written request to the
Document Mail Center for an extension, clearly indicating the assigned 510(k) number and the
additional time requested.  The time period for the extensions is not open-ended and will be
determined on a case by case basis.  If the deficiencies are such that the FDA believes a firm
cannot respond completely within 30 days, the FDA will notify the sponsor and immediately delete
the 510(k) document.
14 3.  In your response, clearly indicate the assigned 510(k) number on the supplemental information
and include a restatement of the deficiencies (or append a copy of the deficiency letter) with a
complete response. The FDA expects a response to address each issue identified in the
deficiency letter and will not evaluate a grossly incomplete response.  If you submit a less than
comprehensive response, the FDA may place the file on hold again after notifying the sponsor or
may raise new questions that must be addressed.  Therefore, in order to minimize the review
time, respond fully to requests for information.
 
15 III.  FORMAT AND CONTENT
III.A.  Cover Letter and Introductory Information
Consult the guidance document on the preparation of a Premarket Notification 510(k), available from
the Division of Small Manufacturers Assistance (DSMA), before beginning work on the 510(k)
document.  This guidance document for liquid chemical sterilants/high level disinfectants is a
supplement to the 510(k) guidance document.  Include a cover letter clearly indicating, in a subject
title, that it is a premarket notification [510(k)] submission. Include the following information as part of
the cover letter or in separate sections:
1.  the trade name or proprietary name of the device
2.  the common, usual, or classification name of the device (e.g., liquid chemical sterilant/high level
disinfectant)
 
3.  the establishment registration number, if applicable, of the owner or operator submitting the
510(k)
 
4.  the FDA product code: MED
 
5.  the FDA review panel code: INCB
 
6.  a classification statement (e.g., unclassified or Class II; see the Proposed Rule classifying liquid
chemical sterilants/high level disinfectants as Class II devices)
 
7.  for a chemical germicide that is indicated for use only with a specific reusable device (e.g., an
endoscope), the name of the reusable device along with its FDA product code, if known
 
8.  the name of the legally marketed predicate germicide(s) to which substantial equivalence of the
device is claimed
 
9.  the name, address, and telephone number of the individual or individuals who may be contacted
regarding the submission; The FDA discusses the 510(k) only with those individuals designated
by the firm as official contacts for the 510(k) submission.
III.B.  Table of Contents
Include a table of contents that notes the section titles and pages.
III.C.  Information Required by the Safe Medical Devices Act of 1990
Under the Safe Medical Device Act of 1990, a 510(k) must include either (1) a summary of the safety
and effectiveness information in the 510(k) upon which an equivalence determination could be based
[510(k) summary], or (2) a statement that safety and effectiveness information will be made available
to interested persons upon request [510(k) statement].  In addition, persons who submit a 510(k) must
certify that, to the best of their knowledge, all information is truthful and accurate and that no material
fact has been omitted (Truthful and Accurate Statement).
The FDA delineates regulations establishing the requirements for the 510(k) summary, the 510(k)
statement and the Truthful and Accurate Statement in 21 CFR 807.92, 807.93, and 807.87(k),
16 respectively.  In addition, in accordance with the Center for Devices and Radiological Health (CDRH)
policy, a 510(k) submission must include a statement of the device indications for use using a
separate sheet of paper.  Provide the following documents:
1.  a 510(k) summary (see 21 CFR 807.92) or statement (see Appendix D)
2.  the Truthful and Accurate Statement (see Appendix C)
3.  an Indications for Use Statement (see Appendix E)
III.D.  Comparison of the New Germicide to the Predicate Germicide
Include a detailed summary table comparing the new germicide to the predicate germicide(s) with
respect to physical and chemical properties, microbiology, toxicology, residues, reusable device
compatibility, chemical indicators, and intended use (see 21 CFR 807.87(f)). 
III.E.  Authorization for Data Access
1.  If you cite data and/or information on file with another agency, include authorization from that
agency for the FDA to access the data and/or information.
2.  If you refer to data and/or information found in a device master file held by another firm, include
documentation from the holder authorizing use of the file.
III.F.  Physical and Chemical Properties
III.F.1.  Description of the Germicide
Provide the following information:
a.  a statement of the product formula with tolerances as it is manufactured (e.g., in a format as
provided in the Environmental Protection Agency (EPA) Confidential Statement of
Formulation (CSF) for pesticides [see Appendix H]; other formats with the same information
may also be used)
 
b.  the upper and lower limits and nominal concentration for each ingredient in the final finished
product; the upper limit is the maximum (and the lower limit is the minimum) amount of the
ingredient that will be present in the product at any time while it is in commerce (i.e., over its
shelf life)
 
c.  the chemical name and Chemical Abstracts Service (CAS) number, of each active ingredient,
intentionally added inactive ingredient, and any impurities that may be present in the product
 
d.  the trade or proprietary name for all ingredients
e.  the Material Safety Data Sheet (MSDS) for each component or ingredient
f.  the purpose or function of each ingredient
g.  a complete description of the product (e.g., single container germicide or a germicide with
separate buffer and activator containers that are mixed prior to use)
17 h.  the microbicidal mode of action of the final product formulation of the germicide, if known, with
references
i.  a thorough discussion of how the formulation was developed and how the specifications/
upper and lower limits were established - In the discussion, include the rationale for the
presence and concentration of each ingredient.  For example, explain the rationale from in
vitro, simulated-use, and clinical-use tests (primarily stability, microbiology, and chemistry
tests) that gauge factors such as the following:
1)  expected inherent degradation of all ingredients during storage and use
 
2)  potential dilution during reuse
 
3)  inactivation by organic matter, oxidation and reduction of the active ingredients,
exposure to heavy metals, etc.
4)  added safety factors
5)  pH buffering requirements and the buffering capacity of components
6)  minimum effective concentration endpoint from dose response studies and/or minimum
recommended concentration at which efficacy has been demonstrated, based on
simulated- and in-use testing (Please refer to Section III.H.4 below for details on
simulated- and in-use testing.)
III.F.2.  Accessory Devices or Containers/Closure Systems
a.  Identify any accessory devices or containers specified in the labeling for use with the
sterilant/high level disinfectant for heating, aerating, etc.
b.  Describe compatible materials for containers that may be used to hold the germicide during
sterilization or disinfection of reusable medical devices. 
c.  In order to address the effect of the container/closures on the germicide stability, provide a
complete description of the germicide container(s)/closure(s) including container sizes,
identity of materials, and specifications. 
d.  A separate guidance document  addresses endoscope reprocessors.  (Call DSMA to obtain
copies of the guidance document, Guidance on Premarket Notification [510(k)] Submissions
for Automated Endoscope Washers, Washer/Disinfectors, and Disinfectors Intended for Use
in Health Care Facilities.)
III.F.3.  Stability Data
Submit stability data obtained under the storage conditions and recommended use patterns specified
in the labeling to support the following claims, as appropriate:
 
  the expiration date (shelf life) of the unopened marketed stock product(s)
18   the use period of the opened and/or activated product
  the reuse life of a product with reusable claims
 NOTE:  Because this guidance addresses the stability of the microbicidal activity and toxicity of
the product under the data requirements for efficacy and toxicity, these data need not be
reiterated here. 
a.  General Considerations for Stability Testing
 
 Because most liquid chemical sterilants/high level disinfectants are unstable at elevated
temperatures, accelerated stability testing may not be appropriate.  Therefore, stability
studies should address the real time stability and dynamics of the formulation during storage,
under conditions specified in the labeling, and during use of the product from an analytical
chemistry perspective (i.e., any chemical/physical changes in the germicide expected or
known, based upon analytical data). 
 
1)  Evaluate the chemical composition and physical properties of the germicide, such as
color, odor, and clarity, and assess the suitability of the container. 
2)  Compare the pH and percentage amount of each active and inactive ingredient present
in the product and activated solution at each time point with the initial specifications for
the product. 
3)  Assess the presence and amounts of any impurities initially present or created in the
stock or activated product during storage. 
4)  Address the effect of all possible neutralizing or interfering physico-chemical factors,
such as temperature fluctuations, humidity, and light, on the stability of the product and
the way in which these factors are controlled, as applicable.
5)  For stability studies supporting the expiration date (shelf life) of the unopened container,
store containers under the conditions indicated in the labeling and analyze samples of
the unactivated and activated products throughout the test period. 
6)  For stability studies supporting the use period of a product after it is opened, store
unopened containers under the conditions indicated in the labeling to the expiration
date. Following the initial analysis, store the opened container to the end of the
proposed use period under the conditions indicated in the labeling and handled in a
manner that reflects actual use conditions of the product.  For example, the storage
conditions should reflect the products sensitivity and exposure to the environment when
the container is accessed repeatedly during the use period for removal of solution.
7)  For stability studies supporting the use period of an activated product with no reuse
claim, store unopened containers to the expiration date under the conditions indicated in
the labeling. If applicable, then store the opened container to the end of the proposed
use period under the conditions indicated in the labeling and handle it in a manner that
reflects actual use conditions of the product.  Following analysis of the unactivated
product and activated product(s), store the activated product under the conditions
indicated in the labeling to the end of the proposed use period, handled in a manner that
19 reflects actual use conditions of the product and then reanalyze the solution. 
8)  For studies supporting the reuse period, store unopened containers to the expiration
date under the conditions indicated in the labeling.  Following analysis of the unactivated
and activated product(s), stress the activated product over the reuse life period using a
simulated reuse protocol (e.g., the EPA reuse protocol).  Then store and handle the
product under conditions indicated in the labeling for the activated product and then
reanalyze the solution.
9)  Obtain stability data with each type of container and closure system proposed for
marketing.  For each type of container and closure system, include the largest and
smallest size containers in the study.  Establish the compatibility of the product for each
container and closure system.  Assess the possibility of interaction of leachables from
the container with the product during storage.  Evaluate each container and closure
system to determine if the system remains intact and inert in the presence of the
chemicals during the shelf life period under the stated storage conditions.
10)  If a component of a germicide contains a microbiological preservative, then provide
antimicrobial effectiveness data using microbial challenge tests, such as the USP
Antimicrobial Preservative Effectiveness test, or by performing chemical assays for the
preservative.  At the minimum, conduct this testing at the beginning and end of the shelf
life period, the use period, and the reuse life period, as applicable.  If you use a chemical
assay instead of an effectiveness test on an ongoing basis, then provide data correlating
effectiveness with content at the end of the shelf life period.
b.  Sampling Plan and Times for Stability Testing
 
1)  Establish a sampling plan, including justification of sample size and the randomly
selection method of sampling.  To represent batch-to-batch variability, select
containers from at least three different lots for each time point, and select each lot
from a different production run.  The test samples should represent the lot as a
whole.  For example, starting at a random point, select every nth container; the
number of sampling times and the size of the lot determine n.  Analyze at least two
aliquots from each sample container. 
2)  Sample frequently enough so that any degradation can be characterized
adequately and the nature of the degradation profile can be determined with
reasonable assurance.  For example, to determine the shelf life, analyze samples
every three months for the first year, every six months for the second year, and
then yearly thereafter.  Sample more frequently if you expect a product to
degrade rapidly or if little information is available to support the stability of the
product.
3)  For a new germicide not currently on the market, provide all available stability
data that support the label shelf life.  In lieu of complete stability data supporting
the proposed claims, the FDA accepts a detailed protocol and sampling plan, as
described below, for ongoing stability studies to be continued after clearance. 
Keep all stability data on file in accordance with the Quality System Regulation, 21
CFR Part 820.
4)  Provide the following detailed information about the sampling plan, the test
20 protocols, the methods of verification, and the methods of analysis: 
 
i)  references to any standards, guidelines or regulations used as a basis for stability
testing 
ii)  the initial, intermediate, and final composition and physical properties of the
germicide
iii)  any other analytical data, such as pH
iv)  the storage conditions (that coincide with labeling)
v)  the identification number and the manufacturing date of each lot
vi)  the size of each lot
vii)  the number of samples selected per lot
viii)  the method used for selecting the samples
ix)  the number of aliquots analyzed per sample
x)  the method used for taking the aliquots
xi)  the time points for analysis
xii)  the dates of sampling and analysis
xiii)  the duration of the study
xiv)  calculations and the statistical analysis
xv)  plots and graphs
xvi)  any stability information from previous formulations obtained during product
development or in the published scientific literature
III.G.  Labeling
 
III.G.1.  Introduction
Submit a draft of the label affixed to the germicide immediate container (bottle label) and any other
draft labeling, such as a draft package insert containing additional information, that may accompany
the germicide.
 
 It is the primary responsibility of reusable device manufacturers to include verified reprocessing
instructions in the labeling for their device, including use of compatible liquid chemical germicides,
when appropriate.  For information on validating device reprocessing instructions, see the April 1996
guidance document entitled, Labeling Reusable Medical Devices for Reprocessing in Health Care
Facilities:  FDA Reviewer Guide, available through DSMA.
 
21  The FDA is actively pursuing the improvement and harmonization of device labeling.  The current
reality is that labeling for many reusable devices does not include either reprocessing instructions or
specifics on use of liquid chemical germicides.  For this reason germicide labeling should stand alone
by providing adequate directions for use to the user.  Notwithstanding the current situation, all
germicide labeling should refer the user to the reusable device labeling for additional directions.
 
III.G.2.  Background
 
 The FQPA exempted liquid chemical sterilants/high level disinfectants used on critical and semicritical
devices from the definition of a pesticide under Federal Insecticide, Fungicide and Rodenticide Act
(FIFRA).  The EPA no longer regulates these products; the FDA is the sole regulatory authority.  The
EPA released Pesticide Regulation Notice, PR 98-2, advising registrants of the FIFRA provisions for
liquid chemical sterilant products that are intended for use on critical and semicritical devices. The PR
Notice states that no EPA references should appear in the labeling for FDA-regulated liquid chemical
sterilants.  Consult the PR Notice for additional guidance regarding label modifications stipulated by
the EPA per the FQPA. Therefore, the EPA bottle label, previously utilized for liquid chemical
sterilant/high level disinfection products, is no longer appropriate.   Liquid chemical sterilants for other
uses and general purpose disinfectants remain EPA-regulated. 
Since the EPA and the FDA operate under different statutes, each agency adopted a different
approach to regulating the labeling claims. The EPA's labeling regulation under FIFRA (Section
2(q)(2)(A)) as defined in 40 CFR Section 156.10 dictates the content and format of the bottle-affixed
label for pesticide products.  Hence, in 1991 when the FDA began actively regulating liquid chemical
germicides, the agency chose not to change the EPA bottle labels to minimize regulatory confusion. 
The FDA recommended that manufacturers prepare a package insert bearing additional information
for users about the use of liquid chemical germicides for reprocessing medical devices. The FDA
described the recommended content of the package insert in its January 1992 draft guidance
document for liquid chemical germicides.  Consequently, the FDA-recommended package insert
contains different information than the EPA-regulated bottle label.  Although both pieces of labeling
include abbreviated directions for use, indications for use, precautions, and warnings, only the FDA-
recommended package insert includes contraindications, information on selecting germicides, detailed
instructions for use, information on re-use and monitoring microbial activity of the product, and
material compatibility.
The two agencies also use different terminology in their labeling.  The FDA adopted the terminology
used by the Centers for Disease Control and Prevention (CDC), which uses the Spaulding
Classification scheme to describe the effect of germicides (i.e., low level disinfectant, intermediate
level disinfectant, high level disinfectant, and sterilant), as shown below:
 Critical devices are introduced directly into the bloodstream or contact a normally sterile tissue
or body space during use; sterilize these devices between uses.
 
 Semicritical devices contact intact mucous membranes and do not penetrate the blood barrier
or otherwise enter normally sterile areas of the body; sterilize these devices between uses
whenever feasible, but high level disinfection is minimally acceptable.
 
 Noncritical devices or instrument surfaces make only topical contact and do not penetrate intact
skin; intermediate or low level disinfect these devices.
 
 The EPA uses other terminology, such as hospital disinfectant, which is equivalent to a low level
22 disinfection claim, and hospital disinfectant with tuberculocidal activity, which is equivalent to an
intermediate level disinfection claim.  The EPA does not have a term that is equivalent to high level
disinfection.  In addition, the EPA allows a product to list on the label specific types of organisms (e.g.,
virucidal, fungicidal, etc.) against which the product is effective, while the FDA relies upon the broader
disinfection terms, as defined by Spaulding, to indicate the product effectiveness. For example, the
FDAs term high level disinfectant indicates that the product is virucidal, fungicidal, tuberculocidal,
bactericidal, and able to kill some spores. 
 
 The agency believes that the label information and format should be consistent from product to
product and should be consistent with the concepts and terminology used by the FDA, the CDC and
the infection control community. Since the FDA has sole regulatory authority over these products, the
agency now recommends that the bottle label contain all the essential information needed by the user
for the safe and effective use of the product and that the package insert contain supplemental
information for the user.
III.G.3.  Content of Labeling
 
 The labeling for liquid chemical sterilants/high level disinfectants must comply with Section 801.5 of 21
CFR that requires adequate directions for use.  Consult the labeling regulation before preparing
product labeling. Manufacturers should provide clear, informative labeling to the healthcare
community.  Therefore, in addition to the information delineated in 21 CFR Sections 801.1, 801.4,
801.5, 801.6, and 801.15, the FDA recommends that the bottle and package insert contain the
information described below. In the germicide labeling, refer the user to the reusable device labeling
for detailed information on how to reprocess the device properly.
 
 During the early 1990s when the products were in regulatory transition from the EPA, the FDA
permitted a product to list on the label specific types of organisms (e.g., virucidal, fungicidal, etc.)
against which the product is effective.  These terms (virucidal, fungicidal, etc.) should be phased out
and should not appear in the labeling for liquid chemical sterilant/high level disinfectant products now
solely regulated by the FDA.  Provide user information on microbial lethality in the package insert. 
 
 In addition, it has been a FDA labeling policy not to include references to specific diseases, such as
AIDS, in advertising, labeling or supporting documents for a device unless effectiveness is proven by
clinical trials.
III.G.4.  Bottle Label
 
 Include information that is essential to the user in the bottle label.  Clearly state the directions for use
and the contact conditions.  Include the following information on the bottle label:
 
a.  product name
 
b.  contents, ingredients and nominal concentrations of active and inactive
ingredient(s)
c.  name and address of manufacturer and/or distributor
 
d.  intended use
Base each claimed level of germicidal activity on supporting potency, simulated-use and in-
use test data and address each in the label.  Make the user aware of the limitations of a
23 device sterilization claim for a liquid chemical germicide. 
Sample statements of intended use
1)  For a device high level disinfection claim supported by potency, simulated-use and in-
use test data:
 
"TRADE NAME is a high level disinfectant intended to disinfect reusable heat-sensitive
medical devices which contact mucous membranes when used (state minimum
recommended or effective concentration(s), contact time, temperature, etc.)."
2)  For a device sterilization claim supported by potency, simulated-use and in-use test
data: 
"TRADE NAME is a liquid chemical sterilant intended to sterilize reusable heat-sensitive
medical devices which contact normally sterile areas of the body when used (state
minimum recommended or effective concentration(s), contact time, temperature, etc.)."
 
e.  Warnings
 
 Describe any serious adverse reactions and potential safety hazards or limitations in use
imposed by the germicide product.  Include the steps that should be taken in case of contact
with the germicide or presentation of a hazard. 
 
f.  Precautions
 
 Identify any personal protective equipment that must be worn, facilities that must be used,
and any other precautions the user should take to safely use the product.  Include all
materials, devices and other agents, such as cleaning agents that are not compatible with the
germicide.  Include statements similar to those shown below:
1)  Clean devices thoroughly prior to disinfection or sterilization to remove all blood and
patient material that may inactivate the active agent.  If all material is not removed, the
germicide may not be effective and infection in the next patient may result.
2)  Rinse devices thoroughly following disinfection or sterilization to remove toxic residues.
3)  DO NOT use with the following heat-sensitive devices: [List any heat-sensitive devices
that have been shown to be incompatible with the product.]  Testing has shown that
TRADE NAME is not compatible with these devices
4)  DO NOT use with the following materials: [List materials that have been shown to be
incompatible with the product.]  Testing has shown that TRADE NAME is not compatible
with these materials
5)  DO NOT use with any heat-stable devices.  Due to the inherent limitation of using liquid
chemicals for sterilizing medical devices, TRADE NAME is limited to reprocessing only
critical devices that are heat-sensitive and incompatible with other sterilization methods.
6)  DO NOT use beyond XX days even if the concentration of the active agent(s) is above
the Minimum Recommended (or Effective, as applicable) Concentration as indicated by
24 the recommended monitoring system. Do not rely solely on days in use. Use patterns may
reduce the established reuse life of the liquid chemical sterilant.  The concentration of the
active ingredient should be evaluated before each use with an appropriate chemical
indicator.
 
g.  Contraindications
State any contraindications.  Contraindications are conditions under which the germicide
should not be used because the risk of use clearly outweighs any possible benefit.
h.  Adverse Reactions
  Identify possible adverse reactions following exposure to the product.
i.  Adequate Directions for Use
 
1)  Detail the preparation and use of the germicide including type of acceptable diluent, the
method of activation or dilution, and the acceptable covered container(s) for (re)use of
the germicide (e.g., stainless steel, plastics, heat bath, etc.).
2)  Provide general instructions for cleaning devices in preparation for sterilization or high
level disinfection.  Refer the user to the reusable device labeling for the manufacturers
recommendations for device decontamination.
3)  Provide the directions for sterilization and/or high level disinfection of cleaned devices in
the prepared solution.  Inform the user of the necessary elements for the sterilant/high
level disinfectant to be effective:
  clean the devices thoroughly
  immerse the devices in the solution
  use a solution that is at or above the minimum recommended or effective
concentration of the active ingredient(s)
  use the solution according to the Directions for Use
4)  Provide detailed rinsing and neutralizing instructions, when needed, including the type of
rinse and duration and/or volume of rinse necessary to remove residues as determined
from testing.  Define the quality of the rinse water, such as pH, presence of dissolved
organic material, water hardness, microbial content, and temperature, in the labeling.  
State any factors in the rinse water that could interfere with adequate removal of
germicide residues from devices.
5)  Provide directions for reuse of the solution, if applicable.  Direct the user to monitor the
solution before each use for the minimum recommended or effective concentration(s) of
the active ingredient(s), time, pH, and temperature, as applicable. Emphasize the need
for monitoring the concentration of the active ingredient(s) of the germicide preparation
before each use and that the decision to use the germicide product should be based on
the concentration of the active ingredient(s) and not the days in use.  Include a
25 statement similar to the one shown below in the directions for use:
 "TRADE NAME can be reused for XX days provided the required conditions for use
(concentration of the active agent(s), pH, time, and temperature) exist based on
monitoring with a chemical indicator, pH test kit, timer, and thermometer. 
 
j.  Chemical Indicator
Provide information about the chemical indicator that is to be used with the reusable product
for monitoring the MEC or MRC of the product active ingredient(s) during the reuse period.
k.  Storage Conditions and Expiration Date
1)  State the expiration date of the stock solution. 
2)  State that the product should not be used after the expiration date.  For a product that is
opened repeatedly for removal of solution, state that the product (from an opened or
unopened bottle) should not be used after the expiration date.  For a product with
reusable claims, state that the product, activated or unactivated, should not be used
after the expiration date.
3)  State the storage conditions of the stock solution, opened container, activated solution,
and use-dilution, as applicable.
4)  State the use period for the opened container, activated solution and use-dilution, as
applicable.
l.  Trained Personnel
 
 Provide a statement noting that the user should be adequately trained in the reprocessing
(decontamination and sterilization or disinfection) of medical devices and in the handling of
toxic substances, such as liquid chemical germicides.
 
 
m.  Emergency and Additional Information
 
 Provide a telephone number for emergencies or for additional information.
 
n.  Disposal
 
 State the method for disposal of the germicide and any neutralizers.  Direct the user to check
local and state regulations for hazardous waste disposal procedures.
III.G.5.  Package Insert
 
 In addition to the information described above for the bottle label, provide the following information in
the package insert:
 
a.  Germicide Classification Scheme for Labeling Purposes
Briefly describe the Spaulding classification scheme as adapted by the FDA. Because liquid
26 chemical sterilants/high level disinfectants are for use with critical and semicritical devices
only, limit the discussion of the classification scheme to critical and semicritical reusable
devices.  For example, use the following statements:
 
  Critical reusable devices must be sterilized between uses. 
 
  Semicritical reusable devices should also be sterilized between uses whenever possible,
but at a minimum, high level disinfection is acceptable.
 
  A sterilant is an agent that destroys all viable forms of microbial life, when used
according to labeling. 
 
  A high level disinfectant is a germicide that inactivates all microbial pathogens, except
large numbers of bacterial endospores, when used according to labeling.
 
b.  General Information on Selection and Use of Germicides for Medical Device 
Reprocessing
 
 Provide a general statement such as the following:
 
 "Choose a germicide with the level of microbicidal activity that is appropriate for the reusable
medical device.  See the labeling for the reusable device or contact the reusable device
manufacturer for further instructions."
c.  Material and Device Compatibility
 
1)  Note the materials that are compatible and incompatible with the germicide as determined
from the literature and/or testing. 
2)  Describe the conditions under which material samples were tested.
3)  Include a statement indicating that material sample testing may not reflect compatibility of
the germicide with finished medical devices. 
4)  If types of medical devices are listed as compatible with the germicide, then describe the
conditions under which the device(s) was/were tested and refer the user to the labeling of
the reusable device for additional instructions.
d.  Mode of Action of Germicidal Activity
Briefly describe what is known about the microbial mode of action of the final product
formulation of the germicide.
e.  Precleaning Agent Compatibility
 
 Note any cleaning agents or cleaning methods that are compatible or incompatible with the
germicide as determined from the literature and/or testing.
 
f.  Toxicology and Adverse Reactions
 
27  Provide a brief toxicity profile of the final product formulation of the germicide and/or the
active ingredient(s) and note possible adverse reactions following exposure to the product.
 
III.H. Efficacy Data
 
 ALL OF THE TESTS DESCRIBED IN THIS SECTION SHOULD ADDRESS THE WORST CASE
COMPOSITION CONDITIONS AS DEFINED BELOW, UNLESS OTHERWISE NOTED.
III.H.1.  Introduction to Microbiological Qualification Tests
 
 Using the data and information in a 510(k), establish that the subject germicide is substantially
equivalent to a predicate germicide (i.e., it has the same intended use and is as safe and effective as
a legally marketed predicate when used according to the labeling).  The FDA recognizes the value of
using comprehensive, scientifically sound performance review criteria in order to help ensure that
these products are safe and effective for their intended use.  To support high level disinfection and
sterilization efficacy claims, the FDA recommends a three-tiered testing regime, including potency
tests, simulated-use tests (tests of inoculated instruments) and in-use tests (tests of clinically-used
instruments).
 
III.H.2.  Study Report Content
 
 The FDA expects that the protocols and data submitted to support the effectiveness of liquid chemical
sterilants/high level disinfectants meet the highest standards for valid scientific studies, that is, at least
as rigorous as for publication in peer reviewed scientific journals.  In general, include the following
information in the study reports:
a.  a clearly stated objective(s)
b.  the study protocol including details on the reagents, apparatus and operating technique,
such as the following:
 
1)  identity of the test organism according to American Type Culture Collection (ATCC)
code or other means that will precisely specify its taxonomic identity and origin, and a
brief culture history of each organism
 
2)  care and preparation of microbial test organisms and execution of resistance tests
3)  description of the germicide solution, such as age, lot number, whether or not it was
stressed, concentration of the active ingredient(s), etc.
 
4)  complete inoculation protocol including the following information: 
 
  concentration of the organism in suspension
 
  the number of organisms theoretically applied to the device
  the number of organisms that can be recovered from the device
 
  the sites of inoculation
 
  the volume ratio of inocula to germicide for a suspension test
28 5)  protocols for microbial recovery with verification data for the methods
6)  protocols for quantitating the wash-off factor with verification data for the methods
7)  protocols for neutralization of the germicide with verification data for the methods
8)  culture/subculture media and other solutions
9)  glassware, dishes, bottles, and other apparatus
10)  incubation devices, conditions, and procedures
11)  organism transfer devices
12)  exposure conditions (duration, temperature, pH)
13)  description of any carriers
14)  all controls
 
c.  detailed results, thoroughly analyzed, with graphs and tables
d.  summaries of the findings that are supported by the test results
 
 Demonstrate the reproducibility of each test method or reference a standard test.  Explain all
variances from the reference tests.  Thoroughly analyze the data and include statistical
evaluations whenever possible.  The FDA recommends that the protocols be designed with
sufficient samples and replicates to ensure statistical significance at the 5% level with statistical
power of at least 90%. 
III.H.3.  Potency Tests
Potency tests are conducted to demonstrate the potential use of the products for high level
disinfection or sterilization of medical devices by establishing a broad spectrum of microbicidal activity
of the test germicide.  The potency tests recommended in this document are standardized benchmark
tests that allow products to be compared one to another.  For all potency testing, demonstrate product
performance under worst case conditions and according to the labeled recommendations for use,
reuse, etc., as described below:
 
a.  Verify the germicide effectiveness under worst case conditions, including temperature
extremes, and other factors as appropriate, such as light, which may affect the efficacy of the
germicide.
 
1)  Worst case conditions for a single use germicide - a germicide from a production run,
stored to expiration and at its minimum specifications (diluted, if necessary).
 
2)  Worst case conditions for a reused germicide - a germicide from a production run, stored
to expiration, stressed to the end of its claimed reuse life, and diluted to its minimum
recommended or effective concentration, if necessary.  Incorporate into the simulated
reuse protocol any factors that may impact the performance of the germicide, such as an
29 organic load, dilution, water quality, temperature variation, and pH changes.
 NOTE: 
 
  The EPA Re-use Test Protocol is an example of a simulated reuse protocol.
  If product that has been stored to the end of its shelf life is not available, contact the
FDA to discuss the use of the oldest product available for testing.
 
III.H.4.  Simulated-Use and In-Use Tests
 
a. Introduction
 
 A chemical germicide can be effective as a high level disinfectant or sterilant only if it comes
in contact with the surfaces of a contaminated device and when the required contact
conditions of time, pH, temperature, and any other critical variables are met.  Potency tests
demonstrate the potential use of the sterilant for sterilization or high level disinfection of
medical devices.  Simulated-use tests, on the other hand, help determine the penetrating
capability of the germicide and other factors that prevent or limit contact and effectiveness of
the germicide, i.e., the tests help identify conditions under which the germicide will fail. 
Simulated-use tests are controlled tests that allow the precise application of a
specified and quantified inoculum to selected device surfaces.
 
 Simulated-use testing intends to establish an adequate safety margin for the use of the
product in/on actual medical devices.  Some device designs are difficult to adequately clean
and some device designs and materials favor biofilm formation on devices, complicating
cleaning (Kaczmarek, et. al., 1992; Costerton, 1997).  This test helps to establish more
refined contact conditions for high level disinfection or sterilization of devices.
 
 Because a simulated-use test on the performance of medical devices is a laboratory method,
it cannot anticipate all outcomes during clinical use.  Therefore, the FDA recommends in-use
tests to confirm the results of simulated-use testing.  The FDA believes that the persistence
and resistance of ambient bioburden, such as biofilms, including wild microbial strains and
other unforeseen factors, may impact the effectiveness of the germicide and limit correlation
of simulated-use tests to actual use conditions.
 
b.  Content tips
1)  Report all available and relevant simulated-use or in-use performance data, both
positive and negative, such as studies conducted by the applicant, data published in the
scientific literature, and studies by reusable medical device manufacturers. 
2)  Summarize the data and justify how the data support a finding of substantial
equivalence. 
3)  Demonstrate that the germicide, when used according to label contact conditions, meets
labeling sterilization and/or high level disinfection claims under both simulated-use and
in-use conditions. 
4)  Comparative tests conducted with the predicate device may not be needed.  If special
circumstances arise, the FDA may request additional testing with the predicate device.
30 5)  Document all failures and analyze each for causation.
6)  The labeling (e.g., limitations on use, adjustments to conditions of use, precautions, etc.)
should reflect the findings of the simulated-use and in-use tests.
7)  If verified reprocessing instructions are available, provide the reusable device labeling to
confirm that labeling refers to the subject germicide (by trade name or type), and to
confirm that comprehensive instructions exist (how well the germicide and device labeling
mesh). When labeling for a reusable device includes verified reprocessing instructions,
then redundant simulated-use and in-use tests by the germicide manufacturer on these
reusable devices may not be necessary.  In this case, germicide labeling can refer the
user to the reusable device labeling for more specific instructions. Refer to the April
1996 guidance document, "Labeling Reusable Medical Devices for Reprocessing in
Health Care Facilities" for further instructions (available from DSMA).
 
c.  General Considerations of Testing
 
 Include the following elements in the test battery for simulated- and in-use studies:
 
1)  Incorporate devices with configurations that impede cleaning and penetration of
germicides (e.g., small lumens, mated surfaces, and hinges).  In lieu of these device
features, or in case of sterilization or disinfection failures, the labeling should exclude
use of the germicide on devices with these features.
 
2)  Incorporate devices with the type of materials indicated in labeling as compatible.
 
3)  Test replicate devices to obtain reliable results.  Use a sufficient number of samples
and replicates to ensure confidence in the results, if statistical testing methods are not
to be used.  Submit a rationale for the number and type of reusable devices selected.
4)  Provide a description of the verified microorganism recovery method.
 Identify the minimum number of organisms that can be detected by the recovery
method.
 Demonstrate that the media will support abundant growth when inoculated with low
numbers of the test organisms, whether normal (10 cfu or less) or injured (100 cfu or
less).
 Verify that the incubation period is adequate to allow for growth.
 Verify that the neutralization method has no germicidal effect and does not otherwise
interfere with the microbicidal activity of the germicide.
 Use the same lot of media throughout testing.  If a new lot of media is introduced,
reverify the test method. 
 Demonstrate a recovery of at least 90% of the injured organisms with the media.
 
5)  Submit test reports indicating the compatibility of the germicide with any cleaning and
31 defoaming agents indicated in labeling of reusable medical devices.
6)  Include appropriate concurrent controls.
The FDA recommends that you use the germicide lots used in the AOAC Sporicidal Test for
the simulated- and in-use studies.
d.  Simulated-use Testing
Consider the following additional elements when planning and conducting simulated-use
testing:
1)  Test semicritical devices, such as flexible endoscopes, to support a high level
disinfection or sterilization claim.  If the labeling indicates the use of the sterilant with
specific devices, then test those devices.
2)  Incorporate other factors into the test that impede cleaning and germicide activity, e.g.,
a representative inorganic and organic challenge added to the inoculum. Include an
organic challenge representative of the type of worst case organic load to which the
device is exposed during actual use, such as serum, blood, and secretions, and may
remain associated with the device following cleaning.  Although 5% BSA and hard
water are commonly referenced as examples of organic and inorganic challenges,
respectively, provide justification for their use in simulated-use testing. Consult the
FDA for further information about what type of challenge to use in simulated-use
testing.
3)  Describe the microbial challenge and the device inoculation method in detail. Inoculate
the most difficult areas for the germicide to penetrate and contact and then allow the
inoculated device to dry.  Quantify the inoculum on the device and the wash-off factor
to determine the actual challenge to the germicide.
4)  Stress and age the germicide solution and dilute the solution to its MRC or MEC, if
necessary.  Following exposure to the solution for the sterilization or high level
disinfection contact time noted in the labeling, remove the test device and rinse, brush,
and then rinse again according to the verified organism recovery method.   Culture all
rinses and brushes with the growth media that has been shown to support growth of
low numbers of organisms.
e.  In-use Testing
Conduct in-use testing in a clinical setting using multiple devices and in conjunction with the
facility personnel who have been instructed to clean the device according to the reusable
device label or the hospital protocol, when they are more specific.  Direct the personnel to
reprocess and rinse the test devices according to germicide label instructions. Employ no
extraordinary methods of device preparation prior to exposure to the germicide, and
conduct testing using fresh solution or under worst case conditions. Use the germicide
solution as described in the labeling.  Quantify the microbial challenge on a representative
control device before and after cleaning the control devices. 
If the processed reusable devices are retreated with a legally marketed germicide before
being returned to service, then in-use testing of germicides in health care facilities can be
32 considered nonsignificant risk studies under 21 CFR Part 56, which do not require prior
FDA approval under the Investigational Device Exemption (IDE).
III.H.5.  High Level Disinfection Claim
Support the high level disinfection claim with efficacy data from potency tests and with simulated and
in-use tests as outlined below.
a.  Potency Tests
1)  FDA defines a high level disinfectant as a sterilant used under the same contact
conditions except for a shorter contact time.  Therefore, products with high level
disinfection claims should first qualify as a sterilant by passing the Association of
Official Analytical Chemists (AOAC) Sporicidal Test (Sporicidal Activity of Disinfectants,
AOAC 6.3.05:1995, Official Method 966.04) as a sterilant, i.e., no failures in the full
test with three separate product lots and under worst case conditions of germicide
composition (as defined in Section III.H.3.a) when used according to labeling.  Please
note that the FDA will not accept partial AOAC Sporicidal Activity tests.
  Submit a study report showing the results of complete testing.  In the testing, include
60 carriers, representing each of two types of surfaces (porcelain penicylinders and
silk suture loops). Test a total of 720 carriers or 240 carriers per product sample. 
Test the germicide against spores of both Bacillus subtilis ATCC 19659 and
Clostridium sporogenes ATCC 3584 on three product samples representing three
different batches.  Use a contact time in the test that is comparable to the
sterilization contact time for the claimed predicate germicide. 
  Obtain results of confirmatory tests conducted by an independent laboratory using
one of the three lots used in the initial AOAC Sporicidal tests. When the FDA began
actively regulating liquid chemical germicides in the early 1990s, we recommended
efficacy testing that was consistent with the EPA efficacy data requirements for
sterilizing or sporicidal agents (EPA DIS/TSS-9, July 11, 1985).  Because
precedence has been established, the FDA continues to recommend that the AOAC
Sporicidal Test be conducted with a total of 720 carriers as described above.
  Compare the AOAC Sporicidal Test contact times of the tested germicide and a
legally marketed germicide consisting of a similar active ingredient.  If there are
significant differences between the contact times of the claimed predicate germicide
and the new germicide, provide scientific justification, such as survivor curve
analysis and the supporting data.  Provide justification for the contact times by
considering the practicality, material compatibility and microbicidal activity of the
germicides.
  Perform the AOAC Sporicidal Test as written in the most recent edition of the
standard test recognized by the FDA.  In a few special cases, a sponsor may
consider deviations from the AOAC test, if they are scientifically justified.  Consult
the FDA prior to initiation of such testing.
2)  Once the product qualifies as a sterilant, conduct an additional potency test using the
same contact conditions used for the AOAC Sporicidal Test except at a shorter contact
33 time, as recommended in the labeling, in order to determine the time required to kill 106
organisms of an appropriate mycobacterium species, i.e., Mycobacterium bovis or
Mycobacterium terrae.  Use an alternative representative mycobacterium species if
you can demonstrate with test data or literature references that the resistance of the
organism to the chemical is similar to Mycobacterium tuberculosis var. bovis.  The FDA
recommends the modified (quantified) Tuberculocidal Activity of Disinfectants (AOAC
6.3.06:1995, Official Method 965.12) or a quantitative suspension test (Ascenzi et al.,
1987).  
 Conduct testing with the mycobacterium in suspension or on carriers, but quantify the
number of organisms on the carriers. 
 Run control carriers concurrently with the test group.
 Conduct testing with two of the three lots of product used for the AOAC Sporicidal
Test.
3)  Submit study reports describing the microbiological lethality profile of the germicide
under worst case conditions of germicide composition (See III.H.3.a).  Use a contact
time in each test shown below that is comparable to the contact time for the claimed
predicate germicide.  The proposed high level disinfectant should pass the following
additional tests under the test conditions defined in the method noted:
 Fungicidal Activity of Disinfectants Using Trichophyton mentagrophytes (AOAC
6.3.02:1995, Official Method 955.17) - Conduct testing with one of the three lots of
product used for the AOAC Sporicidal Test.
 Testing Disinfectants Against Salmonella choleraesuis, Staphylococcus aureus, and
Pseudomonas aeruginosa, Use-Dilution Methods (AOAC 6.2.01:1995, Official
Methods 955.14, 955.15, and 964.02)  Conduct testing with one of the three lots of
product used for the AOAC Sporicidal Test.
 Virucidal Tests previously recommended by the EPA for its germicide registration
program (DIS/TSS-7, November 12, 1981)  Conduct testing with one of the three
lots of product used for the AOAC Sporicidal Test.
For a list of the FDA recognized voluntary standard methods and supplemental
information on these standard methods see http://www.fda.gov/cdrh/modact/steril.html.
 If testing was conducted according to these protocols, the firm may declare conformity
to the recognized standard method and state any deviations from the standards that
may apply (see Abbreviated 510(k) as described in Appendix B).
b.  Simulated-use Testing
See Section III.H.4 for information about simulated-use testing.  Use the most resistant
mycobacterium species as the test organism.  To support a high level disinfection claim, a
test germicide should be able to kill at least 106 inoculated mycobacteria under the
recommended contact time.  For example, the FDA expects no survivors if the test device is
challenged with a 6 log inoculum of mycobacterium. If failures occur, document and analyze
each failure for causation, and then reevaluate the proposed label contact conditions for
34 the high level disinfection claim.
c.  In-use Testing
See Section III.H.4 for information about in-use testing.  Conduct in-use testing according to
the label contact conditions for device high level disinfection.  The FDA expects no
surviving organisms from devices used for testing.  If failures (i.e., surviving organisms
recovered) occur, document and analyze each failure for causation, and then reevaluate
the proposed label contact conditions for the high level disinfection claim.
 
III.H.6.  Sterilization Claim
 
 The survival kinetics for thermal sterilization methods, such as steam and dry heat, have been studied
and characterized extensively, whereas the kinetics for sterilization with liquid chemical sterilants are
less well understood.  The information that is available in the literature suggests that sterilization
processes based on liquid chemical sterilants, in general, may not convey the same sterility assurance
level (SAL) as sterilization achieved using thermal or physical methods (Spaulding, 1971; Favero,
1995).  The data indicate that the survival curves for liquid chemical sterilants may not exhibit log-
linear kinetics and the shape of the survivor curve may vary depending on the formulation, chemical
nature and stability of the liquid chemical sterilant.  In addition, the design of the AOAC Sporicidal Test
does not provide for quantification of the microbial challenge.  Therefore, sterilization with a liquid
chemical sterilant may not convey the same sterility assurance as other sterilization
methods.
 
 One of the primary differences between thermal and liquid chemical processes for sterilization of
devices is the accessibility of microorganisms to the sterilant.  Heat can penetrate barriers, such as
biofilms, tissue, and blood, to attain organism kill, whereas liquids cannot adequately penetrate these
barriers.  In addition, the viscosity of some liquid chemical sterilants impedes their access to
organisms in the narrow lumens and mated surfaces of devices (Muscarella, 1998).  Another limitation
to sterilization of devices with liquid chemical germicides is the post-processing environment of the
device.  Devices cannot be wrapped or adequately contained during processing in a liquid chemical
sterilant to maintain sterility following processing and during storage.  Furthermore, devices may
require rinsing following exposure to the liquid chemical sterilant with water that typically is not sterile. 
Therefore, due to the inherent limitations of using liquid chemical germicides for sterilizing medical
devices, the FDA recommends that liquid chemical sterilants be limited to reprocessing only critical
devices that are heat-sensitive and incompatible with other sterilization methods.
 
 The FDA believed at the time it began actively regulating liquid chemical sterilants/high level
disinfectants that these solutions were primarily used for high level disinfection of devices and were
only rarely used for sterilization of devices. Therefore, the FDA accepted device sterilization claims
based only on AOAC Sporicidal Test data, as allowed by the EPA for sterilant registration. It now
appears that an increasing number of germicide manufacturers intend to recommend their products
for sterilization of heat-sensitive critical and semicritical devices.  Therefore, the FDA now
recommends that simulated-use testing with a calibrated bacterial spore inoculum suspended in an
organic/inorganic challenge and actual-use testing be conducted to support a device sterilization
claim.  Establish the recommended conditions for device sterilization by liquid chemical sterilants as
described below:
 
a.  Potency Tests
1)  Submit a study report showing that a germicide formulation claimed as a sterilant
35 passes the AOAC Sporicidal Test as a sterilant as described in Section III.H.5.a.1.
2)  Submit study reports describing the microbiological lethality profile of the germicide.
The proposed sterilant, used under worst case conditions for germicide composition,
should pass the following additional tests under the conditions defined in the method
noted:
  Modified (quantified) Tuberculocidal Activity of Disinfectants (AOAC 6.3.06:1995,
Official Method 965.12) or a quantified suspension test (Ascenzi, 1987)  Conduct
testing with two of the three lots of product used for the AOAC Sporicidal test.  (See
Section III.H.5.a.2)
  Fungicidal Activity of Disinfectants Using Trichophyton mentagrophytes (AOAC
6.3.02:1995, Official Method 955.17)  Conduct testing with one of the three lots of
product used for the AOAC Sporicidal Test.
  Testing Disinfectants Against Salmonella choleraesuis, Staphylococcus aureus, and
Pseudomonas aeruginosa, Use-Dilution Methods (AOAC 6.2.01:1995, Official
Methods 955.14, 955.15, and 964.02)  Conduct testing with one of the three lots of
product used for the AOAC Sporicidal Test.
  Virucidal Test previously recommended by the EPA for its germicide registration
program (DIS/TSS-7, November 12, 1981)  Conduct testing with one of the three
lots of product used for the AOAC Sporicidal Test..
For a list of the FDA recognized voluntary standard methods and supplemental
information on these standard methods see http://www.fda.gov/cdrh/modact/steril.html. 
If testing was conducted according to these protocols, you may choose to declare
conformity to the recognized standard method and state any deviations from the
standards that may apply (see Abbreviated 510(k) as described in Appendix B).
b.  Simulated-use Testing
See Section III.H.4 for information about simulated-use testing.  Use the most resistant
spore-forming species, i.e., Bacillus subtilis as the test organism for simulated-use testing.
To support a device sterilization claim, the test germicide should be able to kill at least 106
challenge spores under the recommended contact time.  Therefore, the FDA expects no
survivors if the test device is challenged with an inoculum of 6 logs of spores. Document
and analyze all failures for causation.  PLEASE NOTE:  A SAL cannot be inferred for a
device sterilization claim based on this recommended testing protocol.
c.  In-use Testing
See Section III.H.4 for information about in-use testing.
For a product with a sterilization claim alone, conduct in-use testing according to the
label contact conditions for device sterilization.  The FDA expects no surviving organisms
from devices used for testing. If failures occur (i.e., surviving organisms recovered),
document and analyze each failure for causation, and then reevaluate the proposed label
contact conditions for the sterilization claim.
36 For a product with both device sterilization and high level disinfection claims,
conduct in-use testing according to the label contact conditions for high level disinfection.
The FDA expects no surviving organisms from devices used for testing.  If no failures occur,
then FDA may waive in-use testing at the longer contact time to support the device
sterilization claim.  If failures occur, document and analyze each failure for causation, and
then reevaluate the proposed label contact conditions for the sterilization and high level
disinfection claims. 
III.H.7. Summary of Microbiological Test Data
 
 Provide a table summarizing the microbiological test section along with a comprehensive discussion of
the findings of the tests and how the tests support the labeling claims.
 
 III.I. Biocompatibility
III.I.1.  Introduction
 
 Germicide residues that remain associated with devices following reprocessing may be toxic and may
pose a risk to patients and users.  The residue may be the active ingredients, inert ingredients, by-
products of the ingredients, neutralizer, or derivatives of the treated device.  The amount of residue
that remains may vary depending upon the conditions of use of the germicide, the specific component
materials of the reprocessed device, and the methods used to reduce residuals prior to reuse. 
Therefore, it is important that the residues that remain associated with devices following reprocessing
and rinsing are analyzed and quantified and that the potential health risks that these residues pose to
patients are assessed.  In addition, the user is exposed to the germicide solution while repeatedly
processing devices with the germicide over a long period of time.  Therefore, the potential health risks
that the germicide solution poses to the user from handling the solution also should be assessed.
III.I.2.  Residue Data
 
a.  If the labeling for certain reusable devices includes verified instructions for reducing
germicide residues on the device to a safe level, then in the germicide labeling, refer the user
to additional instructions in the reusable device labeling. 
b.  Because not all reusable devices include verified procedures for reducing residues to a safe
level, provide comprehensive data regarding germicide residues remaining associated with
processed devices.  Expose representative devices to the germicide at the maximum
specified use concentration for the maximum contact time indicated in the labeling before the
items are rinsed.
c.  Although a patient may be exposed to a device for only a very short time, no information
currently is available to describe the rate at which residues may be released from devices
during use.  Therefore, the FDA takes a conservative approach and assumes that all
residues remaining associated with a device are potentially available to the patient or user
during exposure.  The FDA recommends exhaustive extraction of residues from the entire
device following reprocessing with the germicide product (including exposure and rinsing per
the proposed product label).
d.  Describe the residue extraction method and provide scientific justification for the method.
Evaluate the type and amount of remaining residue according to the toxicological evaluation
37 discussed below.  Quantify and evaluate the residues of all germicide ingredients or provide
justification for why analysis of an ingredient is not necessary.
e.  The list of materials tested need not be exhaustive, but include representative devices with
component materials indicated in the labeling as compatible with the germicide.  Test a range
of devices that vary in surface area and configuration.  The broader the scope of reusable
devices indicated in the labeling, the more inclusive should be the test articles. 
f.  Base the information in the labeling (as noted in Section III.G.) upon these data.  Thoroughly
describe the residue reduction step (e.g., rinsing) for all labeled germicide use conditions. 
Do not recontaminate the processed reusable device during this step.
 
III.I.3.  Evaluation of Toxicity
 
 To ensure the safe use of the germicide product and of germicide-treated devices, assess the toxicity
of the germicide solution and of all residues remaining on a reusable medical device following
reprocessing with a germicide.  This information assists the FDA in the evaluation of the potential
health risks to patients and users exposed to the germicide residues and to users handling the
germicide solution. 
 
 During evaluation of residues, consider both the active and inert ingredients.  Identify the residues of
concern and provide justification for excluding any residues.  Provide evidence showing that the
amount of each residue of concern remaining on a device is at a safe, nontoxic level. 
 
 To evaluate the toxicity of the germicide solution and the residues, review the available toxicity data
for the germicide solution and of the identified residual chemicals.  The data may be obtained from
from toxicity studies sponsored by the manufacturers of the active and inert ingredients and from
toxicity studies published in the scientific literature.  Provide copies of all references.  If adequate
information is not already available, then conduct toxicity testing with the product at its maximum
specified use concentration; alternatively, test the individual germicide product ingredients.
 
 The FDA understands that liquid chemical sterilants/high level disinfectants are intended primarily for
use on devices that contact the patient for a limited time (as opposed to implanted devices). To
assess the toxicity of the residues, in general, the FDA notes the following tests using the germicide
product and/or the individual ingredients:
 
  Skin irritation test
  Skin sensitization test
  Cytotoxicity test
  Acute dermal toxicity test
  Hemocompatibility/hemolysis test
  Subchronic dermal toxicity test
 
 Use multiple dose levels of residue components to construct a dose-response curve to which the
actual residue level can be compared during a risk assessment process.  If the data from the above
tests show that the use concentration is nontoxic, then one can assume that the device-associated
residues are also nontoxic. 
 
 The FDA also uses the above tests, excluding cytotoxicity and hemocompatibility/hemolysis tests, to
evaluate the toxicity of the germicide product and potential health risks to the user due to handling of
38 the germicide solution.  The FDA suggests the following additional tests:
 
  Acute oral toxicity test
  Primary eye irritation test
  Acute inhalation toxicity test
  Genotoxicity tests
  Chronic toxicity test
  Reproductive and developmental toxicity tests
 
 Depending on the results of the genotoxicity tests, carcinogenicity testing may also be indicated. 
Conduct all testing with the germicide product at its maximum specified use concentration.
 
 Refer to the ISO 10993-1 and Office of Device Evaluation (ODE) Blue Book Memorandum #G95-1 for
further details on biocompatibility testing of medical devices and to published guidelines and methods
for conducting these tests.  Provide a complete description of the toxicity test methods and cite, in
each study report, any guidelines and methods used for conducting the tests.
 If testing is conducted according to the FDA recognized consensus standards for biocompatibility
testing, then declare conformity to the recognized standard method and state any deviations from the
standards that may apply.  (See the list of the FDA recognized consensus standards for
biocompatibility and supplemental information at the CDRH internet site,
http://www.fda.gov/cdrh/modact/recstand.html#Bio.)
III.J. Device and Material Compatibility Qualification
III.J.1.  Introduction
 
 Liquid chemical germicides used to reprocess devices may damage the devices or lead to
deterioration of the materials, and thus adversely affect the safety and effectiveness of the
reprocessed device. For example, surface cracking or pitting makes the device more difficult to clean
and may cause injury during use (Fuselier and Mason, 1997).  In addition, clouding of the lens of an
endoscope decreases visibility and thus the effectiveness of the device (Babb and Bradley, 1995). 
For these reasons, include data confirming the compatibility of the germicide with medical devices and
component materials that are indicated in germicide labeling as compatible.  The data should address
the effects of the germicide on the functionality, material compatibility, and specifications of the
claimed compatible medical devices and materials. 
 
 To evaluate the compatibility claims for devices/materials or general device and material classes
described in the labeling, review the published literature or information from the device or material
manufacturers for data supporting your compatibility claims.  If the available data from these sources
are inadequate, then conduct compatibility testing to support the germicide labeling claims. Provide
information and/or test data that reflect the label claims for the germicide and the device.  The labeling
for a germicide may include claims of compatibility with general classes of materials (e.g., metals,
polymers), general classes of devices (e.g., endoscopes), specific materials (e.g., polypropylene,
stainless steel), specific devices (specific brand names), or any combination of the above claims.
 
 For any specific reusable device claims, the germicide labeling cannot supersede the reusable device
labeling.  In the germicide labeling, refer the user to the reusable device manufacturer for specific
reprocessing instructions.  Do not identify specific reusable medical devices in the labeling as
compatible with the germicide when the reusable device labeling specifically contraindicates its use. 
For example, labeling for dental handpieces contraindicates the use of liquid chemical germicides for
39 reprocessing the devices.  Therefore, indicate in the germicide labeling that the use of the germicide
with dental handpieces is inappropriate.
 
III.J.2.  Testing for Device/Material Compatibility
a.  Devices and materials to be tested 
Test the type of devices and materials that reflect the claims made in the germicide and
reusable device labeling.  If labeling for a reusable device indicates compatibility with the
germicide, then there is no need to conduct redundant testing on that device, but in the
germicide labeling, refer the user to the reusable device labeling.  Also, direct the user to
contact the germicide or reusable device manufacturer for further information. 
If the labeling for the germicide indicates compatibility with specific materials, then test each
material. When germicide labeling indicates compatibility with a specific class of articles
(devices and/or materials), select test articles that are representative of the class and justify
the selection.
The labeling defines the devices and materials that should be tested.  Therefore, the
broader the scope of devices and materials claimed in the labeling, the broader the potential
testing that should be conducted.  For example, reference to "metal" instruments, or simply
"metals" connotes a range of material possibilities.  The same is true regarding reference to
"polymers" or "elastomers" rather than specific materials such as polyethylene. 
b.  Process life or exposure time 
A factor in all compatibility tests is the duration of compatibility (i.e., the number of times a
reusable device and material can be exposed to a germicide before it fails or is otherwise
unusable).  Devices and materials that are compatible with a germicide are those that are
safe and effective for their intended use after a specified number of reprocessing cycles. 
The acceptable number of cycles depends on many factors such as use requirements.
Assessment of the process life of the devices and materials for compatibility with the
germicide in part c below.  Define an acceptable process life for each device and material
and provide justification.  The devices and materials should meet the process life
requirements.  In some cases, the devices and materials may not exhibit significant,
quantifiable deterioration until after numerous cycles of reprocessing.  In order to minimize
the extent of testing, submit justification for the projected compatibility of the test article
based upon extrapolations.
For compatibility testing, repeatedly expose the test devices to the germicide solution at the
maximum specified use concentration for the maximum contact time indicated in the labeling.
 
c.  Reusable device analysis 
Characterize the effect of repeated processing on the functionality of replicate test devices.
The FDA understands that the germicide manufacturer is not necessarily knowledgeable on
the proper functioning of each reusable device and does not have access to the
specifications for these devices and their component materials.  Therefore, the FDA
encourages the germicide 510(k) sponsor to work with reusable device manufacturers to
evaluate the effect of repeated reuse of the germicide on the device functionality.
40 Although functionality testing on materials alone is conceivable, submit verification data
showing that the test correlates to actual device use.  The functionality parameters are
determined primarily on the basis of specifications or functional requirements for the
reusable device. The methods of functionality evaluation should be quantitative, wherever
possible (e.g., tensile properties, flexural properties, impact resistance, hardness,
compressive strength, color, dimensions, permeability, optical transmission, burst strength,
tear strength, electrical resistance, etc.).  Incorporate into the testing, simulated-use
conditions of the test articles between processes.  Visually examine evidence of material
degradation which is characteristic of each material.  For example, examine metals for
discoloration, corrosion, cracking, crazing, and embrittlement.
 
Extensive published test methods for each parameter noted are available. Refer to the
literature when devising test protocols.  Describe the method of preparation of test
devices/materials and methods and criteria for analysis of each parameter in the report. 
 
III.K. Chemical Indicators for Liquid Chemical Germicides
 
 A chemical indicator for liquid chemical germicides is a monitoring device designed to respond with a
characteristic chemical reaction to the concentration of the germicide active ingredient(s).  Liquid
chemical sterilants/high level disinfectants that are labeled for reuse can be used safely and
effectively only if the user has a chemical indicator available to measure the level of active
ingredient(s).  If a germicide requires an indicator and no legally marketed indicator is available, The
FDA will not find the germicide equivalent.  A chemical indicator for a germicide that is marketed
separately from the germicide requires the submission of a separate 510(k). 
III.K.1.  Description of the Chemical Indicator System
 
 Include complete information on the physical and chemical properties of the chemical indicator. 
Provide the following information:
 
a.  the formulation of the indicator system, including the name of each reactive and unreactive
component and the quantity, proportion or concentration of each reactive ingredient
 
b.  the purpose or function of each component
c.  the chemical principle of the test system, including a diagram of the reaction
d.  substances that interfere with the efficacy of the test system
e.  a complete description of the packaging
f.  a summary and explanation of the test, including the clinical utility, indications for use and
significance of the test
 
III.K.2.  Labeling for Chemical Indicators
 
 Provide the following information in the package insert:
a.  Intended Use - Identify the analyte or test objective and type of procedure, i.e., qualitative,
semi-quantitative or quantitative.
41 b.  Summary and Explanation of the Test - Include clinical utility, indications for use and
significance of the test.
c.  Chemical Principle of the Test Procedure - Include a diagram of the reaction.
d.  Storage and Stability (as applicable)  Include the following information:
 
1)  any limits on exposure to light, heat, moisture, strong acids, bases, heavy metals, etc.
2)  the recommended storage conditions (e.g., temperature, humidity, etc.) for opened and
unopened container, and caution user about variation in storage conditions
3)  the expiration dates of the unopened and opened container
4)  a statement that the indicator strip (from an opened or unopened bottle) should not be
used after the expiration date
5)  a space on the container for recording the date the container is opened
6)  visible indications for reagent instability
e.  Specimen Collection and Preparation
f.  Assay Procedure - Include amount of sample required.
g.  Materials Required - Identify materials provided and materials not provided.
h.  Quality Control Procedures  Provide the following information:
 
1)  commercially available products that should be used for positive and negative controls,
if materials are not provided in the kit
2)  frequency and levels of quality control
3)  directions for interpretation of results of quality control material (satisfactory limits of
performance)
 
i.  Test Results Interpretation - Instruct the user how to determine the assay values by
comparison with either a written description of the color or (preferably) a color chart.
j.  Limitations  Provide the following information:
 
1)  identity of any interfering substances
2)  a caution for users who are color blind, when appropriate
 
k.  Performance Characteristics - Provide the results of the comparison testing as described in
part 4 below.
 
l.  Warnings and Precautions  Provide the following information:
42  
1)  potential safety hazards, e.g., Warning, Toxic Strips.  Contain the following
chemicals:... and cautions regarding ingestion, eye exposure, etc.
2)  a statement that chemical indicators cannot be relied upon or promoted as a means of
verifying the sterilization or disinfection process; chemical indicators can only establish
that a specific factor exists within the specified limits of performance of the indicator.
 
m.  Selected Bibliography
III.J.3.  Performance Testing
 
 Provide performance test data to support the labeling claim that the chemical indicator can accurately
and reproducibly measure the MEC or MRC of the active ingredient(s) in the liquid chemical
sterilant/high level disinfectant.  Include the following information:
 
a.  a detailed summary of the results obtained when comparing the performance of the chemical
indicator with a predicate device or scientifically valid method for detecting the active
ingredient of the germicide, utilizing split samples, and tested under simulated-use conditions
- It is important that the testing demonstrate the failure point(s) for the chemical indicator in
order to establish the margin of safety.
b.  a description of the color development for the periods of time less than and longer than the
time period specified for reading the results or justification as to why a description at such
time points is not necessary
c.  the protocol for determining the shelf life (expiration date) of indicators in unopened and
opened containers under worst case storage and usage conditions as indicated in the
labeling
 
43 III.J.4.  General Considerations for Performance Testing
 
a.  Test replicate indicators to obtain reliable results.  Use a sufficient number of samples and
replicates to ensure confidence in the results.  Submit a rationale for the number and type of
indicators selected.  The FDA recommends that a minimum of three lots be tested with 50-
100 samples for each estimate in order to ensure confidence in the results, if statistical
testing methods are not to be used.
b.  Analyze the results of comparison testing according to the following characteristics:
1)  Comparative Sensitivity - ratio of the number of true positives (TP) to the sum of the
number of true positives and false negatives (FN)           TP    
             TP + FN
2)  Analytic Sensitivity - detection level of a test strip relative to a standard quantitative
analytical test
3)  Comparative Specificity - ratio of the number of true negatives (TN) to the sum of the
number of true negatives and false positives (FP)          TN      
                  TN + FP
4)  Analytic Specificity - extent to which a test strip reacts with one or more substances;
identification of substances that could cause false positive results
5)  Accuracy - agreement between an experimentally determined value and the accepted
reference value
6)  Precision - relative tightness of the distribution of measurements of a quantity about
their mean value, expressed in terms of standard deviation
 
 NOTE:  For more information concerning sensitivity and specificity, please refer to Gail
(1990). For more information concerning accuracy and precision, please refer to Mandel
(1964).
 
c.  Provide the specifications for the test such that the accuracy of a "Pass" or color indication
of sufficient active ingredient falls entirely within the effective range of the active ingredient.
d.  Demonstrate, with testing, the performance of the test system in the presence of possible
germicide solution contaminants, such as detergents and organic and inorganic material.
For example, conduct the testing using the worst-case germicide composition as described
under Section III.H.3.a.
e.  Conduct actual use testing for color and/or hue change analysis using test readers, as
applicable.
44 IV.  CONTACTS AND ADDRESSES
Direct general questions regarding the submission of premarket notifications to the Division of Small
Manufacturers Assistance at (800) 638-2041 or (301) 443-6597 or at
http://www.fda.gov/cdrh/dsma/dsmamain.html
Direct questions regarding this guidance document to the following address.
Chief, Infection Control Devices Branch (HFZ-480)
Food and Drug Administration
Center for Devices and Radiological Health
Division of Dental, Infection Control and General Hospital Devices
Office of Device Evaluation
9200 Corporate Blvd.
Rockville, MD  20850
Phone: (301) 443-8913
45 V.   510(K) CHECKLIST
1.                Cover Letter (Signed and Dated)
 
2.                Table of Contents
 
3.                Indications for Use Form
 
4.                Truthful and Accurate Statement (Signed and Dated)
 
5.                 510(k) Statement or
 
6.                 510(k) Summary
 
7.                Comparison of Germicide to Predicate
 
8.                Physical and Chemical Properties
 
9.                Stability Data
 
10.               Labeling
 
11.               Potency Test Data  _____  High level disinfection   _____ Sterilization
 
12.               Simulated-use Test Data  ____ High level disinfection  _____ Sterilization
 
13.               In-use Test Data   ______ High level disinfection ______ Sterilization
 
14.               Residue Data
 
15.               Toxicity Data
 
16.               Material/Device Compatibility Data
 
17.               Chemical Indicator Labeling
 
18.               Chemical Indicator Performance Data
46 VI.  APPENDIX A
Special 510(k): Device Modification
A Special 510(k) is for manufacturers who intend to modify their own currently 510(k) cleared legally
marketed liquid chemical sterilant/high level disinfectant.  The manufacturer has determined that a
new 510(k) is needed for the modification(s) and the modification does not affect the intended use of
the device or the basic fundamental scientific technology of the device.  The paradigm document
(http://www.fda.gov/cdrh/ode/parad510.html) contains additional detail on eligibility criteria.  The following
modifications are examples of the types of changes to a 510(k) cleared liquid chemical sterilant/high
level disinfectant that the FDA considers eligible for Special 510(k) submissions.  These modifications
are eligible provided test data demonstrate there is no significant change in contact conditions,
stability, retention of residues, or material compatibility and there are no new claims associated with
the changes.
a.    addition, subtraction, or change in specifications of inactive ingredients
b.    changes in containers/closures if product was cleared with incomplete stability data or if the
original 510(k) does not contain an accepted stability protocol
c.    increases in (or widening of) tolerances for active ingredient(s) specifications
d.    elimination of any warnings, precautions or other safety related information
e.    changes to manufacturing methods (same raw materials) that do not alter the cleared final
product specifications
In addition to the basic content requirements of the 510(k) (21 CFR 807.87), include the following
additional information in a Special 510(k) submission:
a.  a coversheet clearly identifying the application as a Special 510(k): Device Modification
b.  the name of the legally marketed (unmodified) device and the 510(k) number under which it
was cleared
c.  items required under Section 807.87 (a)-(f), (h), (j), and (k) including a description of the
modified device and a comparison to the cleared device, the intended use of the device, and
the proposed labeling for the device (see Appendices C and D)
d.  a summary of design control activities - Include the following information:
1)  identification of the Risk Analysis method(s) used to assess the impact of the
modification on the device and its components and the results of the analysis
2)  based on the Risk Analysis, an identification of the verification and/or validation
activities required (including methods or tests used) and documentation that these
activities were performed by the designated individual(s) and that the results
demonstrate that predetermined acceptance criteria were met
3)  identification of any manufacturing process controls added/changed as a result of the
47 modifications to the device (e.g., new work instructions, operator retraining, equipment
re-qualification, new inspection aids, additional sampling, etc.)
4)  identification of changes made to the Device Master Record (DMR) related to the
modified device  provide document number(s) and revision level(s)
5)  documentation of final design review and sign-off of modified device by designated
individual(s)
6)  declaration of conformity with design controls (see Appendix F)
e.  indications for use enclosure (see Appendix E)
48 VII.  APPENDIX B
Abbreviated 510(k), Use of Consensus Standards, Special Controls, and Guidance.  
An Abbreviated 510(k) is for manufacturers who intend to market a new (not a modified) liquid
chemical sterilant/high level disinfectant and who rely upon this guidance document as a special
control and a standard recognized by the FDA. The paradigm document describes the
recommended abbreviated documentation under this option in more detail.  FDA maintains a list of
recognized standards on the CDRH website at www.fda.gov/cdrh/modact/recstand.html. The list is
updated at least annually.
Include the following information in an Abbreviated 510(k):
a.  a coversheet clearly identifying the application as an Abbreviated 510(k)
b.  items required under Section 807.87 (a)-(h), (j), and (k) including a description of the device,
the intended use of the device, and the proposed labeling for the device (see Appendices C
and D)
c.  summary information that relies on a guidance document an/or special control(s), a summary
report that describes how the guidance and/or special control(s) were used to address the
risks associated with the particular device type - (If a manufacturer elects to use an
alternative approach to address a particular risk, sufficient detail should be provided to
justify that approach.)
d.  for a submission that relies on a recognized standard, a declaration of conformity to the
standard  Submit the declaration in accordance with the following (see Appendix G):
1)  Identify any element of the standard that was not applicable to the device.
2)  State if the standard is part of a family of standards which includes collateral and/or
particular parts, a statement regarding the collateral and/or particular parts that were
met.
3)  Identify any deviations from the standards that were applied.
4)  Identify what differences exist, if any, between the tested device and the device to be
marketed and a justification of the test results in these areas of difference.
5)  Provide the name and address of any test laboratory or certification body involved and
a reference to any accreditations of those organizations.
e.  data/information to address issues not covered by guidance documents, special controls,
and/or recognized standards
f.  indications for Use enclosure (see Appendix E)
49 VIII.  APPENDIX C
PREMARKET NOTIFICATION
TRUTHFUL AND ACCURATE STATEMENT
[Refer to Section 807.85(j)]
I certify, in my capacity as [Title], that I believe, to the best of my knowledge, that all data and
information submitted in this 510(k) Premarket Notification Submission is truthful and accurate and
that no material fact has been omitted.
[signature]
------------------------------
[Name]
[Title]
[date]
--------------------------------
Date
50 IX.  APPENDIX D
510(k) STATEMENT
[Refer to Section 807.93]
I certify that, in my capacity as (the position held in company by person required to submit the
premarket notification, preferably the official correspondent in the firm), I will make available all
information included in this premarket notification on safety and effectiveness within 30 days of
request by any person if the device described in the premarket notification submission is determined
to be substantially equivalent.  The information I agree to make available will be a duplicate of the
premarket notification submission, including any adverse safety and effectiveness information, but
excluding all patient identifiers, and trade secret and confidential commercial information, as defined in
21 CFR 20.61.
Certified:  _____[Signed]_____________
                _____[Date]_______________
51 X.  APPENDIX E
INDICATIONS FOR USE STATEMENT
510(K) Number: (if known)
Device Name: [Brand Name]
Indications For Use: The [Brand Name] is used for...
          (PLEASE DO NOT WRITE BELOW THIS LINE  CONTINUE ON ANOTHER PAGE IF NEEDED)       
Concurrence of CDRH, Office of Device Evaluation (ODE)
Prescription Use __________ OR  Over-The-Counter Use ___________
(Per 21 CFR Section 801.109)
52 XI.  APPENDIX F
Declaration of Conformity with Design Controls
Verification Activities
To the best of my knowledge, the verification activities, as required by the risk analysis, for the
modification were performed by the designated individual(s) and the results demonstrated that the
predetermined acceptance criteria were met.
                                                                                              
[Name] [Date]
[Title]
[Company]
Manufacturing Facility
The manufacturing facility, [Company Name] is in conformance with the design control requirements
as specified in 21 CFR 820.30 and the records are available for review.
                                                                                              
[Name] [Date]
[Title]
[Company]
[NOTE:  The above two statements should be signed by the designated individual(s) responsible
for those activities.]
53 XII.  APPENDIX G
DECLARATION OF CONFORMANCE WITH CONSENSUS STANDARDS
This device is certified to comply with the voluntary standards as contained in [identify standard(s)
along with edition date(s)], as specified and so stipulated above, unless and where specifically so
indicated to be at variance with the standard specification, in which case information, data and
analysis, or justification for non-applicability, are provided to fully describe the variance and its impact
on the device and to justify said variance.
            [signature]                        
[Name]
[Title]
             [Date]                              
             Date
When there is a third-party certifying laboratory or certification body, provide the names and
addresses and a reference to any accreditation of each laboratory.  Certification statements should
also be included.
54 XIII.    APPENDIX H
 Attached is a sample EPA Confidential Statement of Formula.
55 56 XIV.     REFERENCES
 
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and Routine Control  Industrial Moist Heat Sterilization.
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tuberculocidal activity of disinfectants.  Appl. Environ. Microbiol. 1987; 53:2189-2192.
3.  Association for Advancement of Medical Instrumentation (AAMI) Standards and Recommended
Practices:  Volumes 1 and 2:  Sterilization, 1995 Edition.
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Infect. Suppl. 1995; 30:543-551.
 
5.  Blackwelder WC.  Proving the null hypothesis in clinical trials. In: Controlled Clinical Trials. 1982;
3:345-353
 
6.  Blackwelder WC.  Similarity/equivalence trials for combination vaccines, combined vaccines and
simultaneous administration.  Annals of the New York Academy of Sciences, 754; May 31, 1995.
 
7.  Block SS.  Definition of terms.  In: Disinfection, sterilization and preservation.  Fourth ed. 
Philadelphia: Lea and Febiger, 1991:18-25.
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517-531.
 
12.  Favero MS and Bond WW.  Sterilization, disinfection, and antisepsis in the hospital.  In: American
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16.  Garner JS and Favero MS.  CDC guidelines for handwashing and hospital environmental control,
57 1985.  Infect. Control 1986; 7:231-235.
 
17.  General Hospital and Personal Use Devices Panel, Thirtieth Meeting, Transcript, July 18, 1995.
 
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Israel, E.  Multi-state investigation of the actual disinfection/sterilization of endoscopes in health
care facilities. Am. J. Med. 1992; 92:257-261.
 
20.  Mandel J. The Statistical Analysis of Experimental Data.  John Wiley and Sons, Inc. 1964.
 
21.  Memorandum of Understanding Between the Food and Drug Administration, Public Health
Service, Department of Health and Human Services and the Environmental Protection Agency,
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22.  Interim measures for the registration of antimicrobial products/liquid chemical germicides with
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24.  ODE Blue Book General Program Memorandum #G95-1, May1. 1995.  Use of International
Standard ISO-10993. Biological Evaluation of Medical Devices Part 1: Evaluation and Testing.
 
25.  ODE Blue Book Memorandum #K97-1 January 10, 1997.  Deciding when to submit a 510(k) for a
change to an existing device.
 
26.  Official Methods of Analysis of the Association of the Official Analytical Chemists.  Ed: Kenneth
Helrich, AOAC Inc. Arlington, VA. 1990; Chapter 6:133-146.
58 27.  Rutala WA.  Guideline for selection and use of disinfectants.  Am. J. Infect. Control 1990 18:99-
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28.  Spaulding EH.  The role of chemical disinfection in the prevention of nosocomial infections. In: PS
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59