Guidance for Industry: Preparing a Color Additive Petition for Submission to the Center for Food Safety and Applied Nutrition for Color Additives Used in or on Contact Lenses

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

May 1, 1997
Dear Contact Lens Care Product Manufacturer or Interested Person:
The enclosed GUIDANCE FOR INDUSTRY--PREMARKET NOTIFICATION (510(k)) GUIDANCE
DOCUMENT FOR CONTACT LENS CARE PRODUCTS represents the special control which
has been determined by the Center for Devices and Radiological Health (CDRH)
of the Food and Drug Administration (FDA) as necessary to provide reasonable
assurance of the safety and effectiveness of class II contact lens care
products (listed below).
This document represents the agency's current thinking on the preparation of
510(k)s for contact lens care products. 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.
The draft guidance was initially provided to the public on April 1, 1996, at
which time the agency requested comments from interested persons. As
discussed at the July 26, 1996, meeting of the Ophthalmic Devices Panel
(Panel), FDA has evaluated the comments received and has revised the guidance
document to incorporate changes resulting from comments determined to have
scientific merit.
PLEASE NOTE THAT THE MAY 1, 1997, DOCUMENT REPLACES THE APRIL 1, 1996, VERSION
AS THE APPROPRIATE GUIDANCE DOCUMENT THAT CONTAINS THE "SPECIAL CONTROLS"
WHICH SHOULD BE FOLLOWED FOR SUBMISSION OF A 510(k). PLEASE READ THIS
DOCUMENT CAREFULLY BECAUSE IT CONTAINS IMPORTANT ADDITIONS, DELETIONS, AND
REVISIONS FROM THE APRIL 1, 1996, VERSION.
The Safe Medical Devices Act (SMDA) requires that the Food and Drug
Administration (FDA) issue an order placing class III transitional devices in
class II if FDA has not determined that the devices must remain in class III.
FDA also requires that appropriate regulatory safeguards (i.e., special
controls) be in effect when reclassification occurs. The order will be
published in the FEDERAL REGISTER announcing the reclassification of soft
(hydrophilic) and rigid gas permeable contact lens care products and heat
disinfection units. Reclassification will be effective 30 days from date of
publication of the order. Devices covered by this reclassification include
generic types of devices as follows:
1. Rigid Gas Permeable Contact Lens Care Products: A rigid gas permeable
contact lens care product is a device intended for use in the cleaning,
conditioning, rinsing, lubricating/rewetting, or storing of a rigid gas
permeable contact lens. This includes all solutions and tablets used
together with rigid gas permeable contact lenses.
2. Soft (Hydrophilic) Contact Lens Care Products: A soft (hydrophilic)
contact lens care product is a device intended for use in the cleaning,
rinsing, disinfecting, lubricating/rewetting, or storing of a soft
(hydrophilic) contact lens. This includes all solutions and tablets
used together with soft (hydrophilic) contact lenses and heat
disinfecting units intended to disinfect a soft (hydrophilic) contact
lens by means of heat.

Page 2 - Contact Lens Care Product Manufacturer or Interested Person
Specific devices covered by this reclassification include:
• Saline Solutions (including dry products/tablets)
• Cleaners (Daily Cleaners and Periodic Cleaners)
• Chemical Disinfecting Products for Contact Lenses
• Multi-Purpose Solutions
• In-Eye Contact Lens Solutions (e.g., Lubricating and/or Rewetting Drops)
• Heat Disinfecting Units
The reclassification order does not apply to such contact lens care products
as contact lens cases and cleaning accessories (e.g., mechanical cleaning aids
and cleaning pads) because these devices have not been separately classified.
In the near future FDA intends to revise 21 CFR 886.5918 and 886.5928 to
include such care products as contact lens cases and cleaning accessories
(e.g., mechanical cleaning aids and cleaning pads). For this reason, we have
included guidance on submitting a 510(k) for these contact lens care products
in the enclosed document.
This guidance should be used for all premarket notification submissions made
after reclassification occurs. Manufacturers should be aware that although
this document represents the special control required by SMDA, it is expected
to be impacted by ongoing policy initiatives within CDRH and FDA's efforts to
harmonize its data requirements with international standards. Any significant
updates or changes in data requirements will be announced at forthcoming
meetings of the Panel. Although comments received to date have been
considered prior to this revision, interested persons may submit written
comments at any time, which will be incorporated in future updates of this
guidance if CDRH determines that they are appropriate. Comments should be
submitted to:
Dockets Management Branch (HFA-305)
Food and Drug Administration
12420 Parklawn Drive, Room 1-23
Rockville, MD 20857
and
Division of Ophthalmic Devices
Office of Device Evaluation
Center for Devices and Radiological Health
Food and Drug Administration
9200 Corporate Blvd.
Rockville, MD 20850

Page 3 - Contact Lens Care Product Manufacturer or Interested Person
The guidance document is available on the CDRH Worldwide web home page at
"http://www.fda.gov/cdrh." You are encouraged to obtain electronic copies;
however, if you are unable to do so, you may obtain a hard copy by faxing your
request to the Division of Small Manufacturers Assistance (DSMA) [fax: (301)
443-8818].
I would like to take this opportunity to thank the Panel members, contact lens
industry and other interested persons for taking the time and effort to
evaluate and comment on this special controls document. In addition, I would
like to thank the members of the Vitreoretinal and Extraocular Devices Branch
and others who have worked extremely hard in preparing this guidance document.
Questions concerning this guidance document may be addressed to James F.
Saviola, O.D., or Muriel Gelles at (301) 594-1744.
Sincerely yours
A. Ralph Rosenthal, M.D.
Director
Division of Ophthalmic Devices
Office of Device Evaluation
Center for Devices and
Radiological Health
Enclosure

Guidance for Industry
PREMARKET NOTIFICATION (510(k))
GUIDANCE DOCUMENT FOR CONTACT LENS
CARE PRODUCTS
This document represents the agency's current thinking on the
preparation of a 510(k) for contact lens care products. 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. The guidance is available on the
Worldwide web on CDRH's home page at "http://www.fda.gov/cdrh."
While this guidance document represents a final document, comments
and suggestions may be submitted at any time for agency
consideration to Dockets Management Branch (HFA-305), Food and
Drug Administration, 12420 Parklawn Dr., Rm. 1-23, Rockville, MD
20857 or by writing to James F. Saviola, O.D., Chief,
Vitreoretinal and Extraocular Devices Branch (HFZ-460), Division
of Ophthalmic Devices, Office of Device Evaluation, Center for
Devices and Radiological Health, Food and Drug Administration,
9200 Corporate Blvd., Rockville, MD 20850. This guidance document
replaces the draft PREMARKET NOTIFICATION (510(k)) GUIDANCE
DOCUMENT FOR CONTACT LENS CARE PRODUCTS, which issued on April 1,
1996.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Center for Devices and Radiological Health
May 1, 1997

PREMARKET NOTIFICATION (510(k)) GUIDANCE DOCUMENT FOR
CONTACT LENS CARE PRODUCTS
TABLE OF CONTENTS
Page
I. INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II. GENERAL MANUFACTURING INFORMATION ....................................14
III. PRODUCT SPECIFIC GUIDANCE.............................................18
A. Salines.........................................................19
B. Cleaners........................................................24
C. Chemical Disinfecting Products for Contact Lenses...............30
D. Multi-Purpose Solutions.........................................38
E. In-Eye Contact Lens Solutions (e.g., Lubricating and/or Rewetting
Drops)..........................................................40
F. Heat Disinfection Units.........................................43
G. Contact Lens Cases..............................................45
H. Contact Lens Accessories
(Mechanical Cleaning Aids and Accessory Cleaning Pads)..........47
IV. MODIFICATIONS OF APPROVED CONTACT LENS CARE PRODUCTS REQUIRING A 510(k))
......................................................................50
V. LABELING .............................................................53
VI. RECOMMENDED TEST METHODS..............................................80
A. Chemistry.......................................................82
B. Microbiology....................................................89
C. Toxicology.....................................................112
D. Clinical.......................................................119
E. Shelf-Life Protocol............................................160
VII. QUESTIONS AND ANSWERS ...............................................163

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I. INTRODUCTION
The Safe Medical Devices Act of 1990 (SMDA) requires that the Food and Drug
Administration (FDA) issue an order placing class III transitional devices
[e.g., contact lens care products such as soft (hydrophilic) and rigid gas
permeable contact lens solutions (including dry products/tablets) and heat
disinfection units] in class II if FDA has not determined that the
transitional devices must remain in class III. The order, issued by FDA, is
effective 30 days after publication in the FEDERAL REGISTER. It includes
reclassification of rigid gas permeable and soft (hydrophilic) contact lens
solutions (including dry products/tablets) and heat disinfection units
(defined in 21 CFR 886.5918, 886.5928, and 886.5933, respectively) from class
III (premarket approval) into class II (special controls). This guidance
document sets forth the general information and special controls FDA believes
are needed to assure the safety and effectiveness of contact lens care
products such as rigid gas permeable and soft (hydrophilic) contact lens
solutions (including dry products/tablets) and heat disinfection units and the
evidence that demonstrates the substantial equivalence of these devices to
legally marketed devices [21 CFR 807.92(a)(3)]. For purposes of this guidance
document, the term "class II" is used to describe a generic type of contact
lens care product. However, each manufacturer [i.e., 510(k) holder] should be
aware that an unapproved individual contact lens care product is not a class
II device until it has been determined to be a class II device by
classification through the premarket notification (510(k)) process.
Definition of Contact Lens Care Products Covered by this Guidance Document:
A. Class II contact lens care products are defined in 21 CFR 886.5918 and
886.5928, and generally include:
• Saline Solutions
• Cleaners (Daily Cleaners and Periodic Cleaners)
• Chemical Disinfecting Products for Contact Lenses (including
Conditioning Solutions for Hydrophobic Lenses)
• Multi-Purpose Solutions
• In-Eye Contact Lens Solutions (e.g., Lubricating and/or Rewetting
Drops)
• Heat Disinfection Units
B. Contact Lens Cases and Contact Lens Accessories (e.g., Mechanical
Cleaning Aids and Accessory Cleaning Pads):
Although contact lens cases and contact lens accessories have not been
separately classified as of the date of this guidance, in the past FDA
has reviewed applications for these devices through the 510(k) process.
The Center for Devices and Radiological Health (CDRH) believes that it
is appropriate to include guidance for submitting 510(k)s for these
devices in this document. At this time the Ophthalmic Devices Panel
(Panel) has recommended that contact lens cases be classified in
class II; however, final classification has not occurred to date. The
remaining unclassified lens care products will be brought before the
Panel for classification in the near future. For this reason we have

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included guidance on information that should be included in 510(k)s for
these devices.
As FDA re-evaluates its data requirements for contact lens care products
and works to harmonize its requirements with international standards,
significant changes in our guidance may be forthcoming. Such changes
may include modifications in test methods, definitions, and especially
in the design of clinical trials for care products, all of which are now
being considered. Any changes in requirements will be announced at
forthcoming meetings of the Panel and copies will be placed on the CDRH
Worldwide web (www) home page at "http://www.fda.gov/cdrh." You are
encouraged to obtain electronic copies; however, if you are unable to do
so, you may obtain a hard copy by faxing your request to the Division of
Small Manufacturers Assistance (DSMA) (see list of fax and telephone
numbers at end of the Introduction section).
Purpose of Document:
This document is intended to provide comprehensive directions to enable a
manufacturer of a contact lens care product to submit a 510(k) that FDA
believes adequately demonstrates whether the device is substantially
equivalent to a legally marketed device.
This document represents the agency's current thinking on the preparation of a
510(k) for contact lens care products. 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. It sets forth
the preclinical and clinical testing that FDA believes would be acceptable to
establish substantial equivalence as required by section 513(i) and 513(f) of
the act.
While use of this document to prepare preclinical and clinical protocols will
not ensure investigational device exemptions (IDE) approval or 510(k)
clearance, following the recommendations of this document should ensure that
the necessary tests are conducted. A substantial equivalence determination
for a 510(k) can be expected to follow if tests are conducted properly, data
are adequately analyzed and presented, applications are submitted in
accordance with applicable regulations, and the test results show that the
contact lens care product is substantially equivalent to a legally-marketed
contact lens care product.
Persons may choose to follow the guidance herein or may follow different data
collection and preparation procedures and protocols. If a person chooses to
follow different collection and preparation procedures and protocols, a person
may discuss the matter in advance with CDRH to prevent the expenditure of
money and effort on an activity that may later be determined to be
unacceptable. If alternate procedures are used, the applicant should be
prepared to demonstrate to CDRH's satisfaction that such procedures
demonstrate the substantial equivalence in terms of safety and effectiveness
to the predicate device.
Guidance is provided on the preclinical and clinical tests which should be
used to demonstrate substantial equivalence. If clinical performance data are

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needed, this guidance provides directions for obtaining an IDE [see
Investigational Device Exemptions (21 CFR 812) section].
The comprehensive guidance document includes matrices and descriptions of the
types of preclinical testing (e.g., manufacturing/chemistry, toxicology, and
microbiology) that should be completed prior to submitting a 510(k) or, if
clinical performance data are necessary to demonstrate substantial
equivalence, prior to seeking IDE approval from an institutional review board
(IRB). The document also includes recommended test methods for meeting these
requirements.
The clinical portion of this document includes the major elements of clinical
performance data collection and suggested methodologies to be included in the
protocol. The clinical protocol is part of the investigational plan that must
be submitted to an IRB in order to obtain approval of an IDE under 21 CFR Part
812.
Other elements of the guidance document include: (1) general information on
the applicable regulations and requirements for labeling of contact lens care
products, (2) requirements for modifications of a legally marketed contact
lens care product (see manufacturing/chemistry, toxicology, and clinical
recommendations), and (3) general information needed in a 510(k) submission.
Preclinical or clinical data in other documents on file with CDRH may be
incorporated by reference into a 510(k). To be referenced, documents such as
IDEs, 510(k)s, premarket approval applications (PMAs) or device master files
(DMFs) should have been submitted by the applicant, or the applicant should
provide CDRH with appropriate authorization from the submitter. This
authorization should be in the form of a letter addressed to the Document Mail
Center, HFZ-401, CDRH, 9200 Corporate Blvd., Rockville, Maryland 20850,
referencing the correct document number.
The Division of Ophthalmic Devices (DOD) should be consulted if questions
remain after reading this document (see list of telephone numbers at end of
Introduction section).
Pertinent Regulations:
The FDA regulations especially relevant to class II contact lens care products
are:
• Device Classes (section 513(a)(1) of the act)
• Establishment Registration and Device Listing for Manufacturers of
Devices (21 CFR 807)
• Premarket Notification Procedures (21 CFR 807, Subpart E)
• Investigational Device Exemptions (21 CFR 812)
• Protection of Human Subjects; Informed Consent (21 CFR 50)
• Institutional Review Boards (21 CFR 56)
• Good Laboratory Practice for Nonclinical Laboratory Studies
(21 CFR 58)
• Determination of Safety and Effectiveness (Defines Valid
Scientific Evidence) (21 CFR 860.7)
• Good Manufacturing Practice for Medical Devices: General
(21 CFR 820)

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• Medical Device Reporting (21 CFR 803)
• Labeling [21 CFR 801 (see Section V, Labeling)]
Each of these regulations is briefly discussed below.
Device Classes [Section 513(a)(1) of the Act]:
Class II devices are subject to both general and special controls. General
controls include the prohibition on adulteration (section 501 of the act);
prohibitions on misbranding (section 502 of the act); banned devices
(section 516 of the act); notification of risks and repair, replacement, or
refund (section 518 of the act); records and reports (section 519 of the act);
restricted devices (section 520(e) of the act), good manufacturing practices
(section 520(f) of the act); registration of establishments (section 510 of
the act); listing of devices (section 510(j) of the act); and submission of a
premarket notification (section 510(k) of the act). Special controls may
include the promulgation of performance standards, postmarket surveillance,
patient registries, development and dissemination of guidelines [including
guidelines for the submission of clinical data in 510(k) submissions in
accordance with section 510(k)], recommendations, and other appropriate
actions as deemed necessary to provide reasonable assurance of the safety and
effectiveness of the device.
Establishment Registration and Listing for Manufacturers of Devices
(21 CFR 807):
Medical device manufacturers, initial distributors (U.S. importers), and
distributors are required to register their establishments by supplying CDRH
with the information required on registration form FDA 2891 (Initial
Registration of Device Establishments). Manufacturers are also required to
list their devices in commercial distribution in the U.S. by completing form
FDA 2892 (Medical Device Listing). Foreign manufacturers may, but are not
required to register; however, they must list their devices. Questions about
registration and listing may be addressed to DSMA (see fax and telephone
numbers at the end of the Introduction section).
Premarket Notification Procedures (21 CFR 807, Subpart E):
Most devices are cleared for commercial distribution or marketing in the U.S.
through the 510(k) process. In this process, the manufacturer makes a 510(k)
submission to CDRH and must receive a letter (order) from CDRH permitting
commercial distribution. This order is based on CDRH's finding the device
substantially equivalent to a device legally marketed in the U.S. The
manufacturer must provide in the submission, among other things, evidence of
such substantial equivalence. What constitutes substantial equivalence is
explained in section 513(i)(1)(A) of the act. Substantial equivalence means
that a device has the same intended use and the same technological
characteristics (i.e., design, material, function, and other similar features)
as the predicate device; or has the same intended use and new technological
characteristics, but it can be demonstrated that the device is as safe and
effective as the predicate device and does not raise different types of
questions regarding safety and effectiveness from the predicate device.
The 510(k) notification requirement applies (21 CFR 807.81): whenever a
manufacturer markets a device for the first time; when there is a change in
the intended use; or whenever a legally marketed device is modified in a way

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that could significantly affect its safety and effectiveness. It is not
intended that a 510(k) be submitted for every change, but only where such
changes could significantly affect safety or effectiveness. CDRH believes
that the manufacturer is best qualified to make the initial determination,
which should be based on the exercise of good judgment, adequate supporting
data, and sufficient documentation in conjunction with general written
policies and guidance from CDRH. The manufacturer should be aware, however,
that if he or she makes a decision not to submit a new 510(k), CDRH can
overrule that decision and take appropriate regulatory action. If a
manufacturer does make a change or modification to the device and does not
submit a 510(k), he or she should document the reason for not submitting a
510(k) in the good manufacturing practice (GMP) device master record and make
it available to FDA upon request.
Subpart E of 21 CFR 807.81 (Premarket Notification Procedures) provides
guidance on the type of changes for which an applicant must submit a 510(k) if
the change could significantly affect the safety and effectiveness of the
device. Additionally, you should contact DSMA (see fax and telephone numbers
at the end of the Introduction section) to obtain a copy of the most recent
CDRH general guidance on changes to an existing device that may require
submission of a new 510(k). Manufacturers should be aware, however, that a
device specific guidance document such as the "GUIDANCE FOR INDUSTRY--
PREMARKET NOTIFICATION (510(k)) GUIDANCE DOCUMENT FOR CONTACT LENS CARE
PRODUCTS" supersedes or provides additional guidance to a CDRH general
guidance involving device modifications that may require submission of a new
510(k). If, after attempting to evaluate the change, manufacturers are still
uncertain about the need for a 510(k), they may write a letter explaining the
changes in detail, referencing the 510(k) number, and mail it to the Document
Mail Center, CDRH (address above).
Once a 510(k) has been submitted, additional information may be requested by
CDRH, in which case the 510(k) application will be placed on hold. A letter
is issued stating that the file will be retained for 30 days while waiting for
the submitter's response. If a response is not received within 30 days, the
510(k) may be deleted. The submitter should respond within 30 days or, if the
30-day period cannot be met, request an extension by letter to the Document
Mail Center, CDRH (address above), referencing the 510(k) number. When CDRH
receives the additional information, the review period begins again. This
happens each time additional information is requested.
Premarket notification review allows CDRH to find not substantially equivalent
(NSE) devices that: (a) present new types of questions of safety and/or
effectiveness relative to the predicate devices; (b) appear to perform less
safely or effectively than legally marketed devices; and (c) have indications
that are a new intended use.
If CDRH determines that a device is NSE, the manufacturer may appeal the NSE
decision, file a reclassification petition, or submit a PMA. When a
manufacturer and CDRH disagree about the NSE decision for a device, the
following applies:
• A 510(k) that is determined to be NSE is automatically classified
into class III, and unless reclassified into class I or II, is
subject to premarket approval. The manufacturer may request

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reconsideration of an NSE decision. The 510(k) Staff may be
contacted for information on how to request reconsideration of an
NSE decision (telephone number at end of the Introduction
section).
• Under section 513(f) of the act, a manufacturer of a class III
device may petition CDRH for reclassification of this device into
class I or class II. CDRH will refer a petition to the
appropriate FDA advisory panel for review and recommendation. The
content and format requirements of a reclassification petition are
in 21 CFR 860.123.
• If determined to be NSE because of lack of performance data, the
manufacturer may resubmit another 510(k) with additional data.
A 510(k) should be dated, and list the applicant's (submitter's) name,
address, contact person (if different from applicant), telephone number, and
must be signed by the applicant. The 510(k) should contain a table of
contents, be submitted in duplicate on standard sized paper with pages
numbered, securely bound (if necessary), and three-hole punched. The
manufacturer should designate in the cover letter that the submission is a
"510(k) notification." All attachments to the 510(k) submission should be
appropriately identified. The general information section should include:
• the trade name (proprietary name) for the device;
• the identification of the predicate or legally marketed device to
which substantial equivalence is being claimed;
• the common name or the classification name (21 CFR 807.87) of the
device;
• a description of the device that is the subject of the 510(k);
• a statement of the intended use of the device;
• a statement of how the technological characteristics of the device
compare to those of the predicate device;
• the establishment registration number [although not required in a
510(k), the applicant will need to register his or her
establishment within 30 days of product release];
• the address of the manufacturing facility/facilities, including
the sterilization site(s);
• the class in which the device has been placed (class I, II, or
III) under section 513 of the act, and, its appropriate panel, if
known (if the submitter determines that the device has not been
classified, a statement of that determination and the basis for
that determination);
• the reason for the premarket notification [e.g., a new device or a
modification to an existing device (if the 510(k) is for a
modification, describe in detail the reason for the modification
and provide the equivalent device's 510(k) number)];

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• compliance with the requirements of the act under section 513
special controls (class II devices);
• copies of draft labeling and available advertising for the device;
• engineering drawings (for care products such as heat disinfection
units, lens cases, etc.);
• under 21 CFR 807.92 and 807.93 the 510(k) submitter must include
either a summary of the safety and effectiveness information upon
which the substantial equivalence determination is based, or a
statement in the 510(k) that the submitter will make available the
safety and effectiveness information to interested persons upon
request. If a statement is provided, it should be (1) dated (2)
signed by the certifier, (3) made on a separate page of the
premarket notification submission, and (4) clearly identified as
"510(k) statement" which contains the following:
"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], of [Company Name], 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."
• a dated and signed statement certifying that the submitter
believes, to the best of his or her knowledge, that all data and
information submitted in the premarket notification are truthful
and accurate, and that no material fact has been omitted in
accordance with 21 CFR 807.87(j).
Subpart E of Section 807 of 21 CFR and the booklet "Premarket
Notification 510(k): Regulatory Requirements for Medical Devices" (HHS
Publication FDA 92-4158) provide detailed explanations and examples of ways
that companies can comply with the 510(k) requirements. DSMA can provide you
with the regulation and this booklet, answer questions, and provide guidance
regarding the regulatory process. DSMA's fax and telephone numbers are listed
at the end of the Introduction section.
Investigational Device Exemptions (21 CFR 812):
Data from clinical testing may be necessary to demonstrate the substantial
equivalence of a contact lens care product to a legally marketed device. To
collect these clinical data, an approved IDE is required before the sponsor
(usually the manufacturer) can distribute investigational medical devices for
clinical testing. The IDE regulation describes procedures for obtaining an

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approved IDE and outlines the responsibilities of a sponsor and an
investigator during a clinical investigation with a medical device.
FDA considers clinical studies of certain solutions intended to be used
directly in the eye to be significant risk investigations which require both
IRB and FDA review and approval prior to initiating clinical studies.
Examples of significant risk investigations include studies of: (1) solutions
containing new types of active ingredients that have no history of ophthalmic
use and cannot be adequately characterized from a safety standpoint by the
preclinical testing contained in this guidance, or (2) solutions containing
biologic or pharmaceutical ingredients that could present a risk to the health
and safety of the subjects, and would involve overlapping jurisdiction with
other Centers within FDA.
FDA considers most clinical studies of contact lens care products to be non-
significant risk investigations since the active ingredients can be adequately
characterized from a safety standpoint by the preclinical testing contained in
this guidance. The abbreviated requirements of the IDE regulation
[21 CFR 812.2(b)] apply for non-significant risk investigations, which
basically require the following:
1. The sponsor must submit and obtain approval for a non-significant
risk device study from a properly constituted IRB (21 CFR 56), or
FDA if no IRB exists (21 CFR 812.62(b)), prior to distributing
devices for a clinical investigation (21 CFR 812.30).
2. All test subjects must give their informed consent (21 CFR 50)
before being treated with the investigational device. Informed
consent is obtained on a written form advising the subjects of
their rights as voluntary research subjects, apprising subjects of
risks, benefits, and alternate procedures, if any, and test
procedures involved.
3. All investigations must be properly monitored.
4. Certain recordkeeping and reporting requirements must be met [see
21 CFR 812.2(b)(1)(v)-(vi)].
FDA review and approval is not required for an investigation of a non-
significant risk device. A sponsor needs to obtain IRB approval and follow
the requirements of 21 CFR 812.2(b)(1)(i) through (vii).
Under the abbreviated requirements for non-significant risk device clinical
studies (21 CFR 812.2(b)), an IRB must determine that a particular contact
lens care product poses a non-significant risk. For a device investigation to
be determined to be non-significant risk, a sponsor must provide an IRB with a
statement of why the investigation does not pose a significant risk, and the
IRB must agree with this assessment. The IRB must also approve the
investigation as a non-significant risk study.
IRBs should be provided with all information necessary to reach a sound
decision. This information, in the case of a contact lens care product,
should include informed consent forms and the clinical protocol. It is
important to note that, in the case of non-significant risk investigations,
although preclinical data are not required to be submitted to CDRH until a
510(k) is submitted, the sponsor should conduct preclinical tests prior to

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initiating a clinical study to predict product performance and to protect the
health of the subjects. The purpose of preclinical tests is to evaluate
whether subjects will be at undue risk, and thus preclinical test results
should be submitted to the IRB for its review prior to testing in humans.
IDE Study Design:
Sponsors of investigations should consider carefully how to adequately
demonstrate the substantial equivalence of their specific devices to legally
marketed devices and design their study to assure that the data provide valid
scientific evidence, as defined in 21 CFR 860.7; to answer all clinical
objectives properly; and to form a sound basis to support the intended use and
claim(s) being made in the labeling.
Manufacturers should carefully review the clinical recommendations in this
guidance document, which have been designed to assist in developing adequate
clinical protocols. In addition, they should consult with the DOD scientific
staff, if necessary, when preparing their clinical protocol. The preparation
of an adequate protocol is one of the most important aspects of the clinical
investigation and essential for a successful 510(k) when clinical performance
data are required to demonstrate substantial equivalence. The protocol should
be designed to fully support the proposed labeling claim(s) and intended use
of the device. The sponsor is responsible for ensuring that the study design
is appropriate and that all necessary tests are completed. If alternative
tests are more appropriate than those listed or additional tests must be
conducted, the overall design of the study and its justification are the
responsibility of the study sponsor.
Information available to sponsors includes the IDE regulation (21 CFR 812) and
related information. Please contact the IDE Staff or DOD for further guidance
(see telephone numbers at the end of the Introduction section).
Protection of Human Subjects; Informed Consent (21 CFR 50):
The fundamental purposes of IRB review and of informed consent are to assure
that the rights, safety, and welfare of subjects are protected. A signed
informed consent form is evidence that the information required by
section 50.25 has been provided to a prospective investigational subject. IRB
review of the form to ensure that the subject is given adequate information
concerning the study serves a dual function: protection of the subject and
documentation that the institution complied with applicable regulations.
Informed consent must be obtained in accordance with the informed consent
regulation, and any informed consent form used must embody the elements of
informed consent required by 21 CFR 50.25. The consent form itself is an aid
to ensure that adequate information is provided to the subject. The signed
consent form provides documentation of a subject's consent to participate in a
study. The entire informed consent process involves giving a subject
information concerning the study, providing adequate opportunity for the
subject to consider all options, responding to the subject's questions,
ensuring that the subject has comprehended this information, and, finally,
obtaining the subject's voluntary consent to participate. Informed consent
must be documented pursuant to 21 CFR 50.27 and is required by 21 CFR 50.20
for all subjects in clinical investigations of medical devices. Specific
questions may be addressed to the IDE Staff (see telephone number at the end
of the Introduction section).

` 10
Institutional Review Boards (21 CFR 56):
An IRB is a board, committee, or other group formally designated by an
institution to review, to approve the initiation of, and to conduct continuing
review of biomedical research involving human subjects in accordance with FDA
regulation. The purpose of IRB review is to assure that:
• risks to subjects are minimized, and are reasonable in relation to
anticipated benefits;
• selection of subjects is equitable;
• informed consent will be sought from each prospective subject or
the subject's legally authorized representative and will be
documented;
• where appropriate, the research plan makes adequate provision for
monitoring the data collected to ensure the safety of subjects;
and
• there are adequate provisions to protect the privacy of subjects
and to maintain the confidentiality of data.
The IRB regulation outlines membership and review requirements. All IRBs must
conform to and comply with all requirements in this regulation.
Specific questions may be addressed to the IDE Staff (see telephone number at
the end of the Introduction section).
Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies (21 CFR 58):
The purpose of this regulation is to assure the high quality of nonclinical
laboratory testing required to evaluate the safety of medical devices.
Sponsors should state in all submissions whether or not nonclinical laboratory
tests were conducted in accordance with this regulation. When procedures are
not conducted in accordance with the GLP regulation, justifications should be
provided.
Specific questions may be addressed to the IDE Staff (see telephone number at
the end of the Introduction section).
Determination of Safety and Effectiveness (Defines Valid Scientific Evidence)
(21 CFR 860.7):
This regulation defines what does and does not constitute valid scientific
evidence for the purpose of determination by FDA that there is reasonable
assurance that a device is safe and effective for its intended use. Although
a 510(k) only requires a demonstration of substantial equivalence to a legally
marketed device, this demonstration is in terms of the device being as safe
and as effective as a legally marketed device and that the device does not
raise different types of questions of safety and effectiveness than the
predicate device.
Specific questions about the interpretation of this regulation should be
addressed to DOD (see telephone number at the end of the Introduction
section).

` 11
Good Manufacturing Practice for Medical Devices: General (21 CFR 820):
The Good Manufacturing Practice (GMP) for Medical Devices General Regulation,
required by section 520(f) of the act, covers the methods used in, and the
facilities and controls used for, the design, manufacture, packaging, storage,
and installation of devices. It covers the following general areas:
organization and personnel; buildings; equipment; controls for components,
processes, packaging, and labeling; device holding, distribution, and
installation; device evaluation; device and manufacturing records; complaint
processing; and quality assurance (QA) system audits.
SMDA amends section 520(f) of the act to authorize the inclusion of
preproduction design validation in the GMP regulation. A revised GMP
regulation was published in the FEDERAL REGISTER on October 7, 1996
[61 FR 52601] that incorporates preproduction design controls.
Specific questions on GMP requirements may be addressed to DSMA (see fax and
telephone numbers at the end of the Introduction section).
Medical Device Reporting (21 CFR 803):
The Medical Device Reporting (MDR) regulation requires all manufacturers of
medical devices to report to FDA within 30 days whenever the firms receive or
otherwise become aware of information that reasonably suggests that one of
their marketed devices: (1) may have caused or contributed to a death or
serious injury; or (2) has malfunctioned and that the device or any other
similar device would be likely to cause or contribute to a death or serious
injury if the malfunction were to reoccur.
Manufacturers and importers of devices are required to establish and maintain
an MDR file and to permit any authorized FDA employee at reasonable times to
have access to, and to copy and verify the records contained in this file.
FDA considers any expression of dissatisfaction, be it oral or written,
regarding identity, quality, durability, reliability, safety, effectiveness,
or performance of a device, to be a complaint. However, not all complaints
meet the MDR reporting criteria.
Copies of the MDR regulation and an FDA publication entitled, "An Overview of
the Medical Device Reporting Regulation," are available by contacting DSMA
(see fax and telephone numbers at the end of the Introduction section).
Management Initiatives:
On June 30, 1993, new policies to improve the device approval process were
announced by CDRH. These new policies are as follows:
• Expedited review: To assure that those devices which represent
major advancements in medical care reach the market without delay,
CDRH has put into effect a "fast track" review system for them.
These device applications will be placed in a separate queue and
not treated under the usual "first-in, first-reviewed" policy.
Included in the expedited review category will be devices used to
treat serious conditions for which no alternative treatments exist
and devices that offer decidedly greater clinical benefits or
lower risks than existing technologies.

` 12
• Refuse-to-accept policy: In the past, inadequate and incomplete
applications wasted a great deal of CDRH's time. Reviewers were
obliged to "re-cycle" these applications, going back to the
company repeatedly to request needed information or to clarify
poorly presented data. To address this problem, the agency has
established a "refuse-to-accept" policy that will specify the
minimum criteria for accepting an application. If these are not
met, the application will be rejected.
Some specific reasons to refuse to accept a 510(k) submission for
contact lens care products would be failure to include
information establishing substantial equivalence, a 510(k) summary
of safety and effectiveness or 510(k) statement, or a truth and
accuracy statement.
• Setting review priorities using risk assessment (previously called
"Triage"): Early in the review process, CDRH will determine the
potential health hazard posed by each device and will focus most
of its attention on those devices that pose a significant risk to
patients. Devices with minimal risk potential will receive a less
extensive review.
To achieve this, three review tiers have been identified:
Tier I - Essentially a focused labeling review for intended
use/indications for use; Tier II - Routine scientific and labeling
review (the majority of 510(k)s will be in this tier); and
Tier III - Intensive scientific and labeling review, using a team
review approach, for all first and second of a kind devices
utilizing new technology or having new intended use(s), as well as
other devices determined by their inherent risk to require an
intensive review.
Contact lens care products, including solutions that incorporate
traditional preservative systems and intended uses, are currently
assigned to a Tier II review.
• Status reports to manufacturers: In the past, device
manufacturers have often not been able to determine the status of
their 510(k) submissions as they proceed through the review
system. This has proven a major source of frustration,
particularly since lack of information can interfere with sound
business planning. To address this problem, CDRH has established
a computerized system through which manufacturers will receive a
status report on their 510(k) submissions within 3 days of
requesting it, if the application has been under review over 90
days.
More information is available on each of these policies in ODE Blue Book memos
available by contacting DSMA (see fax and telephone numbers at the end of the
Introduction section).
Special Controls:
This guidance document sets forth the special controls which have been
determined at this time by CDRH to be necessary to provide reasonable
assurance of the safety and effectiveness of class II contact lens care

` 13
products in the absence of an applicable standard. These special controls
consist of the recommended protocols for the preclinical and clinical data
that FDA believes establish substantial equivalence under section 513 of the
act and identify modifications to contact lens products that FDA believes
would require submission of a new 510(k) and labeling guidance.
CDRH has carefully considered these recommendations, but also recognizes that
it is important to be open-minded about new tests which can be, and are,
suggested. If different procedures are chosen by the applicant, a full
justification should be submitted. The justification should clearly explain
how the alternative procedure can provide the valid scientific evidence needed
to demonstrate substantial equivalence. The absence of any justification and
supporting evidence may mean that the application will be found unacceptable
during scientific review.
DOD may be consulted prior to the initiation of any tests if, after reading
the guidance document, questions remain concerning a specific test
recommendation for a contact lens care product (telephone number listed
below).
Fax and Telephone References:
DSMA: Fax: (301) 443-8818 (For copy of guidance document, refer to shelf
number 674)
Telephone: (800) 638-2041 or (301) 443-6597
DOD: Fax: (301) 480-4201
Telephone: (301) 594-1744
IDE Staff: Telephone: (301) 594-1190
510(k) Staff: Telephone: (301) 594-1190

` 14
II. GENERAL MANUFACTURING INFORMATION
This section of the guidance contains the general manufacturing information
that should be submitted in a 510(k) for contact lens solutions and tablets.
For purposes of this guidance, we have focused primarily on active
ingredients. However, manufacturers should also assess the effects of
inactive ingredients (e.g., buffering agents and tablet coatings) on such
factors as pH, tonicity, solution compatibility, enzymatic activity,
preservative effectiveness, disinfection efficacy, preservative
uptake/release, and critical micelle concentration of surfactant.
In 510(k) submissions, applicants should provide the general information
listed below as well as the information in Section III (Product Specific
Guidance), Section V (Labeling), and other applicable sections of the
guidance. Applicants are reminded that when test data are submitted, complete
reports of the tests as well as summary information should be included in the
510(k).
A. General Manufacturing Information for Contact Lens Solutions and
Tablets:
The applicant should document and summarize the following
manufacturing/chemistry information:
1. Chemical Composition of the Contact Lens Solution or Tablet:
The chemical composition of the contact lens solution or tablet
should include all active and inactive ingredients and their
functions.
Note: For purposes of this guidance:
- An "active ingredient" is generally defined as any chemical
component that is included in the formulation of a contact
lens solution or tablet in sufficient concentration to
achieve the intended purpose of the specific product (e.g.,
a surfactant for a daily cleaner, an anti-microbial agent
for a disinfecting product, an enzyme for an enzymatic
tablet or a preservative for preserved lens care products).
- An "inactive ingredient" is generally defined as any
chemical component other than an active ingredient (e.g.,
buffering agents and water) that is included in the
formulation.
If the components meet United States Pharmacopoeia (USP), National
Formulary (NF), or American Chemical Society (ACS) specifications,
this should be noted. If sorbic acid is used as a component,
aldehyde should be quantified and its specification justified.
For any non-compendial component, the applicant should establish
approved raw material specifications in accordance with GMPs and
submit them in the 510(k) (e.g., characterization data on this
component and/or analytical results from manufacturing batches
used for preclinical and clinical tests).

` 15
When applicable, a side-by-side comparison of the composition of
the new device compared to the predicate device should be
provided. If the new solution or tablet is identical to the
predicate device in terms of concentrations of active and inactive
ingredients, the general manufacturing information can be limited
to a description of the manufacturing process with a flow chart,
demonstration of product sterility and sterilization validation,
shelf-life data, and a description of the packaging, including
tamper resistant features. If the new solution or tablet is not
identical to the predicate device in terms of concentrations of
active and inactive ingredients, all general manufacturing
information outlined below should be addressed in the 510(k).
Whenever new claims are made for a marketed device, supporting
information should be provided.
2. A brief description, including a flow chart, of the manufacturing
process should be provided.
3. Sterility: In accordance with 21 CFR 800.10, all contact lens
solutions should be sterile. Sterility should be demonstrated
using USP <71>, Sterility Tests, or by an equivalently validated
sterility test method. Product sterility or validated package
integrity testing should be performed to support the shelf-life
requested in the 510(k). [Section VI.E (Shelf-Life Protocol)].
For general information and references dealing with the
development and validation of sterilization cycles, manufacturers
should refer to USP <1211>, Sterilization and Sterility
Assurance/General Information. Manufacturers should validate
their product sterilization system(s) and cycle(s) using a
suitable validation method and demonstrate the efficacy and
compatibility with the product and/or container. Manufacturers
should use the most recent edition and include reference(s) for
the validation method in the 510(k). Some additional references
on sterilization validation methods are provided below:
• ANSI/AAMI/ISO 11134: Sterilization of health care products
- Requirements for validation and routine control -
Industrial moist heat sterilization.
• ANSI/AAMI/ISO 11135: Medical devices - Validation and
routine control of ethylene oxide sterilization.
• ANSI/AAMI/ISO 11137: Sterilization of health care products
- Requirements for validation and routine control -
Radiation sterilization.
• ISO/TR 13409: Sterilization of health care products -
Radiation sterilization - Substantiation of 25 kGy as a
sterilization dose for small or infrequent production
batches.
• Validation of Aseptic Filling for Solution Drug Products.
Technical Monograph No. 2. Parenteral Drug Association.

` 16
• Guideline on Sterile Drug Products Produced by Aseptic
Processing June 1991. Prepared by: Center for Drug
Evaluation and Research, Center for Biologics Evaluation and
Research, and Office of Regulatory Affairs, FDA.
• USP <1211> Sterilization and Sterility Assurance of
Compendial Articles: Aseptic Processing.
In accordance with the Office of Device Evaluation (ODE) 510(k)
Blue Book Memorandum #90-1 dated February 12, 1990, the applicant
should provide the following information in the 510(k) submission
to support validation of a traditional sterilizing system [e.g.,
steam under pressure, ethylene oxide (ETO), gamma radiation or
aseptic fill process]:
a. the sterilization method that will be used;
b. a description of the method that will be used to validate
the sterilization cycle, but not the validation data itself;
c. the sterility assurance level (SAL) which the manufacturer
will meet;
d. a description of the packaging to maintain the device's
sterility (this should not include the package integrity
testing data);
e. if sterilization involves ETO, the maximum levels of
residues of ETO, ethylene chlorhydrin, and ethylene glycol
which remain on the device or components of the device
(e.g., bottles or container closure system); and
f. the radiation dose, if radiation sterilization will be used.
Applicants should provide, in the 510(k), a description of the
quality assurance procedures and sterility test methods used to
provide routine sterility assurance.
4. Microbial Limits Test: Manufacturers of nonsterile contact lens
products marketed in dry or tableted formulation should submit
data from USP microbial limits testing to demonstrate acceptable
microbiological quality, when applicable. These data may be
omitted if the manufacturer provides data demonstrating that the
level of the active ingredient concentration is inhibitory.
5. In accordance with 21 CFR 800.10(b), contact lens solutions
packaged in multi-dose containers should be formulated and
packaged as to volume and type of container and appropriately
labeled to afford adequate protection and minimize the hazard of
injury resulting from contamination during use (e.g., preserved
multi-dose solutions, unit-dose containers, discard time periods).
6. Preservative Effectiveness: Manufacturers of preserved solutions
should demonstrate preservative effectiveness initially and at the
shelf-life requested in the 510(k). See Section VI (Recommended
Test Methods) Micro--Appendix A, for guidance on the recommended

` 17
preservative effectiveness test with microbial rechallenge on
day 14.
7. Shelf-Life (Stability) Data Including Product Specifications,
Container and Container Sizes:
Please refer to Section VI E. (Shelf-Life Protocol) for guidance
on establishing, or extension of, shelf-life.
8. Tamper Resistant Packaging: All solutions and tablets must meet
the requirements of 21 CFR 800.12, Contact Lens Solutions and
Tablets; Tamper-Resistant Packaging.
9. Solution Compatibility Under Recommended Care Regimen:
Compatibility of the solution with the lens type (hydrophilic or
hydrophobic) indicated for the product specific use should be
assessed. For guidance, see applicable testing matrix and Section
VI (Recommended Test Methods) Chem--Appendix C.
10. Preservative Uptake/Release: Preservative uptake/release data
should generally be submitted in a 510(k) for a solution
containing new preservatives for contact lens use. When
applicable, manufacturers should assess the effects of inactive
ingredients (e.g., buffering agents, etc.) on preservative
uptake/release. However, a manufacturer may justify omission of
these data in a 510(k) provided:
a. the manufacturer demonstrates that the proposed preservative
system is essentially identical in terms of chemical
composition and intended use (hydrophilic lenses or rigid
gas permeable lenses) to the preservative system of the
predicate device; and
b. the manufacturer demonstrates that the new preservative does
not raise toxicological concerns and the new preservative
carries no charge or the same charge as the lens material
(e.g., generally negatively charged).
CDRH considers hydrophilic contact lenses to represent a worst
case. Therefore, manufacturers who already have SE clearance for
a contact lens care product intended for use with hydrophilic
contact lenses do not need, unless otherwise notified, to submit
additional preservative uptake/release data for adding use with
hydrophobic lenses to labeling.
For guidance, see applicable testing matrix and Section VI (Recommended
Test Methods) Chem--Appendix A, if the above criteria cannot be met.
B. Other Contact Lens Care Products:
Other contact lens care products included in this guidance include heat
disinfecting units, lens cases, and contact lens accessories (e.g.,
mechanical cleaning aids and accessory cleaning pads). See Section III
(Product Specific Guidance) and Section V (Labeling) for guidance on
these devices.

` 18
III. PRODUCT SPECIFIC GUIDANCE
This section is a composite of mini-guidances (hereafter referred to as
product specific guidance) for each of the devices included in the GUIDANCE
FOR INDUSTRY--PREMARKET NOTIFICATION (510(k)) GUIDANCE DOCUMENT FOR CONTACT
LENS CARE PRODUCTS. Each product specific guidance contains its own testing
matrix (when applicable) to provide applicants with a summary chart and
narrative explanation of preclinical and clinical testing recommendations for
collecting performance data. CDRH expects that these data either be submitted
or that the testing areas be addressed in the 510(k), unless the applicant
provides a justification for why the data are not applicable.
The product specific matrices also apply when a marketed product is changed in
a way that could significantly affect its safety or effectiveness [e.g.,
change or modification in the active ingredient(s)]. Applicants are reminded
that when performance data are submitted in a 510(k), data should include full
reports, where applicable, of the test data as well as summary information.
Please note that the information and data elements included in the General
Manufacturing Information section are not repeated in each product specific
guidance section, but are included by reference. In addition, Section V
(Labeling) includes both general and product specific labeling guidance.
Product specific guidances included in this section are:
1. Saline Solutions
2. Cleaners (Daily Cleaners and Periodic Cleaners)
3. Chemical Disinfecting Products for Contact Lenses (e.g., chemical
disinfecting solutions, chemical disinfection systems, and conditioning
solutions).
4. Multi-Purpose Solutions
5. In-Eye Contact Lens Solutions (e.g., Lubricating and/or Rewetting Drops)
6. Heat Disinfecting Units
7. Contact Lens Cases
8. Contact Lens Solution Accessories (e.g., Mechanical Cleaning Aids and
Accessory Cleaning Pads)
The following matrices (including preclinical and clinical guidance) and
Section V (Labeling) set forth the special controls determined by CDRH to be
necessary to assure the continued safety and effectiveness of the devices and
the information that should be provided in a 510(k).
The applicant should compare product active ingredient(s) with those of the
predicate device and refer to the appropriate section of the applicable matrix
for guidance.

` 19
A. SALINE SOLUTIONS
A saline solution is generally defined as a contact lens care product
(e.g., solution, capsule or tablet) containing sodium chloride as the
principal active ingredient in an aqueous based solution formulation to
produce a physiologically balanced saline solution (approximately 0.9%
by weight). These products are either pre-formulated sterile solutions
or packaged as salt tablets or capsules which require distilled water as
a diluent to produce a non-sterile "homemade" saline solution. They are
intended to be used with soft or rigid gas permeable contact lenses for
one or more of the following:
• rinsing after cleaning to remove loosened debris and cleaning
solution
• rinsing prior to lens insertion
• keeping lenses wet during heat disinfection
• storage after disinfection
• a diluent for dissolving lens care tablets (e.g., enzyme or
disinfecting tablets)
• a diluent for use in hydrogen peroxide disinfection systems
(limited use)
Pre-formulated sterile saline solutions can be marketed in formulations
that are preserved or unpreserved; buffered or unbuffered. These
solutions can be packaged in various containers (e.g., aerosols, non-
aerosol, unit-dose or multi-dose).

TESTING MATRIX FOR SAWNE SOLUTIONS
Preservative Effectiveness wich
Xechallenge or
aacteriortasir for Unpreserved
O*,d",,*
Same Active
Ingredirnrs Within
FOOTNOTE A: 	If the saline solution has a pH of 7.2 + 0.2 and tonicity of 290-320 mosmlkg, manufacturers do not need, unless
otherwise notified, to submit solution compatibility data.
klarkered Products 	Marketed Producrs 	Different Acri?e
lame Accive Ingrediems In
Bigher C o ~ c e n r r a c i ~ n sThan
Recommended SireiScope of Clinical
Study 	I 60 subj 11 no
Same Ae:ive 	Ingrcdienzs In
Lover Concearraz:ons Than
1
New Ingredients for
Ophthalmic Use or

` 21
Pre-formulated Saline Solutions:
Manufacturing/Chemistry:
Pre-formulated Sterile Saline Solutions: Pre-formulated sterile saline
solutions are generally maintained in the comfort range (e.g., pH = 6.6-
7.8 and tonicity of 290-320 mOsm/kg) to avoid eye irritation when used
in accordance with the recommended lens care regimen. In addition to
the information listed in the General Manufacturing Information section
and in the matrix, the following information should be provided:
1. Heat Disinfection: If the saline solution is indicated for use
during heat disinfection, the effect of heat disinfection on pH,
tonicity, and preservative concentration should be assessed and
data submitted.
2. Diluent for Lens Care Tablets: If the saline solution is
indicated for use as a diluent for enzyme tablets, tablet
disintegration time and enzymatic activity time profile as
indicated in labeling should be assessed, compared to a control
(e.g., approved diluent), and data submitted.
Microbiology:
This section, Section II (General Manufacturing Information) and the
matrix include microbiological guidance for all pre-formulated saline
solutions.
1. Preservative Effectiveness: Applicants should refer to the
preservative effectiveness portion of Section II (General
Manufacturing Information) and Section VI (Recommended Test
Methods) Micro--Appendix A for guidance. In addition, applicants
should be aware that passing preservative effectiveness test with
rechallenge on day 14 allows manufacturers to label preserved
saline solutions for lens storage up to 30 days following
disinfection. Labeling instructions for 30-day storage in
preserved saline should include instructions for lens case care
and the need to re-disinfect lenses after the recommended storage
time.
Manufacturers submitting 510(k)s for salines preserved with sorbic
acid or sorbate-based preservatives may omit the microbial
rechallenge in preservative effectiveness testing. However,
testing should continue as directed by the protocol in Section VI
(Recommended Test Methods) Micro--Appendix A for 28 days,
including enumeration of surviving microorganisms at 21 and 28
days. In order to support labeling claims for long-term storage
of lenses following heat disinfection (up to 30 days), the 510(k)
should include data demonstrating that passing preservative
effectiveness test results were obtained using a rechallenge on
day 14.
2. Multi-dose saline products may contain bacteriostatic agents
(e.g., boric acid or borate) instead of traditional preservatives.
In lieu of a preservative effectiveness test, a bacteriostasis

` 22
test may be conducted and the product labeled with the appropriate
discard date [see Section VI (Recommended Test Methods) Micro--
Appendix C].
Toxicology:
See Testing Matrix for Saline Solution and Section VI (Recommended Test
Methods) Tox--Appendices A-B, for guidance on recommended tests for
including in a 510(k).
Clinical:
Clinical data are not generally required to be submitted in a 510(k) for
saline solutions provided the saline solution is formulated, packaged
and labeled in an equivalent manner to the predicate device.
Homemade Saline Solutions (Salt Tablets/Capsules System):
A homemade saline solution is made from a salt tablets/capsules system
that generally consists of salt tablets or capsules containing Sodium
Chloride USP and a plastic mixing bottle of a specified size. The
system is packaged with labeling instructions to use over-the-counter
(OTC) distilled water as a diluent for dissolving the salt tablet or
crystals. The prepared saline solution is used with soft (hydrophilic)
contact lenses for rinsing PRIOR to heat disinfection and in the lens
case for keeping lenses hydrated during heat disinfection. See
Section V (Labeling) for guidance on recommended indications for use
statements and warnings.
Chemistry:
Sodium Chloride USP or equivalent is recommended for use in
manufacturing salt tablets or capsules.
Microbiology:
Microbiology testing data are generally not required to be submitted
when a salt tablet or capsule system is formulated using Sodium Chloride
USP, packaged and labeled in an equivalent manner to the predicate
device. Microbial issues are addressed in Section V (Labeling).
Toxicology:
See Section VI (Recommended Testing Methods, Toxicology Testing for
Containers) Tox--Appendix A, for guidance on recommended tests for
including in the 510(k) for the container/closure system for salt
tablets/capsules systems. Toxicology information is generally not
required to be submitted for salt tablets or capsules formulated using
Sodium Chloride USP.

` 23
Clinical:
In the early 1980s, the Ophthalmic Devices Panel recommended and CDRH
concurred, that the unit-dose aspect of the salt tablets/capsules system
is such that clinical testing to establish the safety and effectiveness
of the product would not be needed if the salt tablets/capsules system
is formulated using Sodium Chloride USP, packaged and labeled in an
equivalent manner to the predicate device.

` 24
B. CLEANERS
Daily Cleaners:
A daily cleaner is generally defined as a contact lens care product
containing one or more active ingredients in sufficient concentrations
to loosen and remove loosely held lens deposits and other contaminants
on the surface of contact lenses. A daily cleaner may also be indicated
for use as a component of a lens care disinfection regimen, or as a
labeled intended use for a multi-purpose lens care solution.
Daily cleaners are generally marketed as pre-formulated solutions and
labeled for use in conjunction with digital manipulation (e.g., fingers)
or an accessory device (e.g., mechanical cleaning aids) for a specific
period of time to accomplish the intended purpose. Sufficient data
should be submitted in the 510(k) to support the effectiveness of the
daily cleaner when used for the minimum time period recommended in the
labeling.

` 25
TESTING MATRIX FOR DAILY CLEANERS	TESTING MATRIX FOR DAILY CLEANERS
Same Active Ingredients
Within Marketed
Concentrations
Same Active Ingredients In
Higher Concentrations Than
Marketed Products
Same Active Ingredients In
Lower Concentrations Than
Marketed Products
New Ingredients for
Ophthalmic Use or
Different Active
Ingredient
CHEMISTRY
Stability X X X X
Solution Compatibility X X X X
Cleaning Effectiveness - Critical
Micelle Concentration X X X X
MICROBIOLOGY
Sterility X X X X
Preservative Effectiveness with
Rechallenge X X X X
Microbial Limits Test (Dry
Products/Tablets Only) X X X X
Stability X X X X
TOXICOLOGY
In-Vitro Cytotoxicity X X X X
Acute Ocular Irritation X X X X
Acute Oral Toxicity X
Sensitization X
In-Vivo Ocular Biocompatibility X
CLINICAL
Recommended Size/Scope of Clinical
Study
FOOTNOTE A FOOTNOTE B 60 subj/3 mo
FOOTNOTE A: Clinical performance data may need to be submitted depending on the physical/chemical, microbiological and toxicological data collected
(i.e., a higher concentration of the active cleaning ingredient in a multi-purpose solution with a daily cleaning claim may require
submission of clinical data while an increase in concentration of the active ingredient in a daily cleaner may not). If necessary, a 30
subject/1 month clinical study should be conducted.
FOOTNOTE B: If active ingredient is a surfactant, sponsor may use either appropriate in vitro tests or conduct a clinical test with 60 subject/3 months
to establish the efficacy of the lower concentration of active ingredient.

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Chemistry:
The following chemistry tests are applicable to a daily cleaner containing a
surfactant(s) as the active ingredient. Manufacturers of daily cleaners
containing active ingredients other than surfactants may wish to consult DOD
before initiating test protocols. The information included in Section II
(General Manufacturing Information), the testing matrix, and listed below
should be provided in the 510(k):
1. Surface Tension of the Solution: [See Section VI (Recommended Test
Methods) Chem--Appendix B, for recommended methodology)].
2. Micelle Concentration of the Surfactant in the Solution: [See
Section VI (Recommended Test Methods) Chem--Appendix B for recommended
methodology].
3. Other scientifically valid method: Supporting literature and/or method
validations testing information should be provided.
Microbiology:
See Testing Matrix for Daily Cleaners, Section II (General Manufacturing
Information), and Section VI (Recommended Test Methods) Micro--Appendix A, for
guidance on recommended tests for including in a 510(k).
Toxicology:
See Testing Matrix for Daily Cleaners, and Section VI (Recommended Test
Methods) Tox--Appendices A-B, for guidance on recommended tests for including
in a 510(k).
Clinical:
See Testing Matrix for Daily Cleaners for guidance on size and scope of a
clinical trial. Further clinical guidance on protocol development is
available in Section VI (Recommended Test Methods) Clin--Appendices A-E.
In the absence of validated in-vitro data, applicants are advised that for
cleaning studies (e.g., studies of non-surfactant agents) a cross-over design
with additional in-vitro analysis of worn lenses is an example of one method
to demonstrate substantial equivalence to the predicate device. Sponsors may
choose to consult with DOD prior to developing their protocols.

` 27
Periodic Cleaners:
A periodic cleaner is generally defined as a contact lens care product (e.g.,
solution or tablet) containing one or more active ingredients (e.g., enzymes)
in sufficient concentrations to loosen and remove deposits (e.g., proteins)
from the lens surface and from within the polymer matrix. Periodic cleaners
are recommended for removing lens deposits such as proteins or lipids that
cannot generally be removed from lenses with the use of a daily cleaner.
Periodic cleaners have traditionally been recommended for use on a weekly
basis.
Periodic cleaners are generally marketed as pre-formulated solutions or as
tablets containing the active ingredients. Labeling directions for the
original enzyme preparations derived from pancreatin and papain stated that
lenses should be soaked for a specified time period after the enzyme tablets
are dissolved in diluents such as saline solutions, chemical disinfection
solutions or multi-purpose solutions to release the active ingredients.
Later technological innovations of bacterial enzymes (e.g., subtilisin) have
in some cases combined the enzyme soak with the soaking period of the
disinfection process. Newer pre-formulated solutions are also added during
the disinfection process, but on a daily rather than weekly basis.
Sufficient data should be submitted in the 510(k) to support the effectiveness
of the periodic cleaner when used for the minimum time period recommended in
the labeling. Consideration should be given to the active ingredients
utilized as well as the predicate device labeling for general guidance in
determining the recommended period of use.

` 28
TESTING MATRIX FOR PERIODIC CLEANERS	TESTING MATRIX FOR PERIODIC CLEANERS
Same Active Ingredients
Within Marketed
Concentrations
Same Active Ingredients In
Higher Concentrations Than
Marketed Products
Same Active Ingredients In
Lower Concentrations Than
Marketed Products
New Ingredients for
Ophthalmic Use or
Different Active
Ingredient
CHEMISTRY
Stability X X X X
Solution Compatibility X X X X
Enzymatic Activity X
FOOTNOTE A X
FOOTNOTE A X
FOOTNOTE A X
FOOTNOTE A
MICROBIOLOGY
Sterility X X X X
Preservative Effectiveness with
Rechallenge X X X X
Microbial Limits Test (Dry
Products/Tablets) X X X X
Stability X X X X
TOXICOLOGY
In-Vitro Cytotoxicity X X X X
Acute Ocular Irritation X X X X
Acute Oral Toxicity X
Sensitization X
In-Vivo Ocular Biocompatibility X
CLINICAL
Recommended Size/Scope of Clinical
Study
FOOTNOTE B 30 subj/1 mo 60 subj/3 mo
FOOTNOTE A: An In-vitro cleaning effectiveness test should be conducted statistically, using 30-day human-worn daily wear lenses (e.g., group 1 and group
IV) to assess the effect of reducing enzymatic activity in this device compared to the predicate device with the same active ingredients.
FOOTNOTE B: Clinical performance data may need to be submitted depending on the physical/chemical, microbiological and toxicological data collected
(i.e., a higher concentration of the active cleaning ingredient in a multi-purpose solution with a periodic cleaning claim may require
submission of clinical data while an increase in concentration of the active ingredient in a periodic cleaner may not). If necessary, a 30
subject/1 month clinical study should be conducted.

` 29
Chemistry:
In addition to the information listed in Section II (General Manufacturing
Information) and as outlined in the testing matrix in this section, the
following should be provided. (Consideration should be given to tablet
preparations compared to liquid preparations.)
1. enzyme disintegration time (for tablet) and enzymatic activity time
profile in the proposed diluents as indicated in the labeling;
2. the pH and tonicity of the spent solution when the enzymatic tablet is
dissolved in, or added to, the proposed diluents;
3. if the enzymatic tablet is intended to be dissolved in, or added to, a
chemical disinfection solution for simultaneously cleaning and
disinfecting contact lenses, the effect of the enzyme on the
effectiveness of disinfection should be assessed;
4. in-vitro cleaning effectiveness should be conducted for 30 days using
human-worn daily wear lenses (group I and group IV for hydrophilic
lenses) to assess statistically the effect of reducing enzyme activity
in the device compared to the predicate device containing the same
enzyme; and
5. if the enzyme in the device in the submission is identical to the enzyme
in the predicate device, a side-by-side comparison of the information
requested in items 1-3 should be submitted along with a discussion of
why the safety of the new device and cleaning effectiveness are
equivalent to the predicate device.
Microbiology:
See Testing Matrix for Periodic Cleaners, Section II (General Manufacturing
Information) and Section VI (Recommended Test Methods) Micro--Appendix A, for
guidance on recommended tests for including in a 510(k).
If a periodic cleaner is indicated for use simultaneously with a chemical
disinfecting product, disinfection efficacy testing should be performed with
the periodic cleaner present and data submitted in the 510(k).
Toxicology:
See Testing Matrix for Periodic Cleaners and Section VI (Recommended Test
Methods) Tox--Appendices A-B, for guidance on recommended tests for including
in a 510(k).
Clinical:
See Testing Matrix for Periodic Cleaners for guidance on size and scope of a
clinical trial. Further clinical guidance on protocol development is
available in Section VI (Recommended Test Methods) Clin--Appendices A-E.

` 30
C. CHEMICAL DISINFECTING PRODUCTS FOR CONTACT LENSES
Contact lens disinfection is a critical step in the safe and effective
reprocessing of lenses recommended for reuse. For purposes of this
guidance document, contact lens disinfection is generally defined as a
process that uses one or more contact lens care products designed to
eliminate and destroy potentially harmful microorganisms on a contact
lens. The contact lens disinfecting products that utilize anti-
microbial ingredients for chemical disinfection of lenses are described
below. (Heat Disinfection Units are discussed in Section III.F of this
guidance.)
1. Chemical Disinfecting Solution: A chemical disinfecting solution
is generally defined as a contact lens care product containing one
or more active ingredients (e.g., preservatives or anti-microbial
agents) in sufficient concentrations to destroy harmful
microorganisms on the surface of a contact lens within the
recommended minimum soaking time.
In order for a contact lens care solution to be labeled as a
contact lens "disinfecting solution," it should meet the primary
performance criteria of the stand-alone procedure for contact lens
disinfecting products [see Section VI (Recommended Test Methods)
Micro--Appendix B Part 1 for methodology]. This criteria may also
be satisfied by a hydrogen peroxide (H2O2) disinfecting solution.
2a. Chemical Disinfection System: A chemical disinfection system is
generally defined as a combination of two or more products, when
used in accordance with the labeled directions, results in the
cleaning and disinfection of a contact lens.
In order for the contact lens regimen to be labeled as a chemical
disinfection system, it should at minimum meet the performance
criteria of the regimen procedure [see Section VI (Recommended
Test Methods) Micro--Appendix B Part 2].
A chemical disinfection system (also referred to as a chemical
disinfection regimen) generally consists of a daily cleaning
solution, rinsing solution and soaking solution. Because all
steps within the regimen (cleaning, rinsing and soaking) should be
completed to obtain adequate contact lens disinfection, special
labeling controls are required for these systems [see Section V
(Labeling)].
2b. Disinfecting Systems Requiring Neutralization: Some disinfecting
systems may require specially designed lens vials or neutralizing
solutions. An example of current technology in this area is a
H2O2 system. A H2O2 system is generally defined as a combination
of two or more contact lens care products that, when used in
accordance with labeled directions for use, will result in the
adequate disinfection of a contact lens. H2O2 systems generally
consist of the following:

` 31
a. H2O2 Solution: This product is generally defined as a
contact lens solution containing the active ingredient,
H2O2, in sufficient concentrations to destroy harmful
microorganisms on the surface of a contact lens during the
minimum recommended soaking time. In some cases, H2O2
solution may meet the primary performance criteria of the
stand-alone procedure for contact lens disinfecting products
in Section VI (Recommended Test Methods) Micro--Appendix B
Part 1.
b. Neutralizer: This product is generally defined as a contact
lens care product (e.g., disk, tablet, or solution)
containing one or more active ingredients in sufficient
concentration to neutralize the irritating and toxic effects
associated with the residual H2O2 remaining on the lenses
after soaking in the H2O2 solution. Pre-formulated
neutralizing solutions may also be labeled for use as a
rinsing and storage solution for contact lenses. A
neutralizer is generally considered to be a component of the
whole H2O2 disinfecting system.
c. Lens Vial: In addition, the H2O2 system may also contain a
specially-designed contact lens vial that acts as a lens
case to store lenses during the H2O2 disinfection process.
Many of the currently marketed H2O2 systems are uniquely
designed to use only those components identified in the
labeling for safe and effective use of the system.
3. Conditioning Solution: A conditioning solution is a solution that
may contain multiple active ingredients (e.g., preservative and
ophthalmic demulcents) in sufficient concentration to enhance the
wettability of hydrophobic lenses (i.e., RGP and PMMA) prior to
insertion and to destroy harmful microorganisms on the surface of
the lens during the recommended soaking time.
A conditioning solution should meet, at a minimum, the performance
criteria of the regimen procedure. A conditioning solution may be
recommended for use with a specific daily cleaner as part of a
lens care regimen for soaking and storage of RGP lenses prior to
wear. Because of the multiple claims for this type of solution,
information should be submitted in a 510(k) to support all claims
identified in the labeling for a conditioning solution. These
products may also be used to lubricate and rewet RGP lenses prior
to insertion in the eye.
Manufacturers who wish to provide eye care practitioners with separate
instructions for in-office chemical disinfection and storage of trial lenses
should submit a new 510(k) for the additional labeling. These instructions
should be intended for reprocessing of trial lenses included as part of a
manufacturer's trial lens fitting set or for individual lenses maintained in
the practitioner's inventory for reuse between patients. Because there are
increased risks associated with the reuse of trial lenses between patients,
disinfection and storage claims should be supported by anti-microbial efficacy
data, including virucidal efficacy (e.g., H. simplex, Adenovirus).

` 32
Manufacturers should include the following in their instructions to eye care
practitioners:
• To record the initial storage date and the end of the storage
period
• Reminder that disinfecting solutions remain within their
expiration date during the entire trial lens storage period
• A visual check for turbidity in storage solution that would
indicate contamination
• Instructions for proper care of storage vial to prevent biofilm
At this time, no harmonized industry standards address the issues associated
with in-office disinfection and storage of trial lenses. Professional
associations such as the American Optometric Association and the American
Academy of Ophthalmology publish guidance for practitioners on hygienic
management of trial lenses and in-office disinfection. FDA is currently
working with the International Standards Organization (ISO) to develop a
standardized method to address efficacy criteria and labeling recommendations
regarding the disinfection and storage of trial lenses. Additional guidance
will be provided as it becomes available.

` 33
TESTING MATRIX FOR SOAKING SOLUTIONS FOR DISINFECTION	TESTING MATRIX FOR SOAKING SOLUTIONS FOR DISINFECTION
Same Active Ingredients
Within Marketed
Concentrations
Same Active Ingredients In
Higher Concentrations Than
Marketed Products
Same Active Ingredients In
Lower Concentrations Than
Marketed Products
New Ingredients for
Ophthalmic Use or
Different Active
Ingredient
CHEMISTRY
Stability X X X X
Solution Compatibility X X X X
MICROBIOLOGY
Sterility X X X X
Preservative Effectiveness with
Rechallenge X X X X
Disinfection Efficacy X X X X
Microbial Limits Test (Dry
Products/Tablets) X X X X
Stability X X X X
TOXICOLOGY
In-Vitro Cytotoxicity X X X X
Acute Ocular Irritation X X X X
Acute Oral Toxicity X
Sensitization X
In-Vivo Ocular Biocompatibility X
CLINICAL
Recommended Size/Scope of Clinical
Study
30 subj/1 mo 60 subj/3 mo

` 34
TESTING MATRIX FOR NEUTRALIZING PRODUCTS	TESTING MATRIX FOR NEUTRALIZING PRODUCTS
Same Active Ingredients
Within Marketed
Concentrations
Same Active Ingredients In
Higher Concentrations Than
Marketed Products
Same Active Ingredients In
Lower Concentrations Than
Marketed Products
New Ingredients for
Ophthalmic Use or
Different Active
Ingredient
CHEMISTRY
Stability X X X X
Solution Compatibility FOOTNOTE A FOOTNOTE A FOOTNOTE A X
MICROBIOLOGY
Sterility X X X X
Preservative Effectiveness with
Rechallenge X X X X
Microbial Limits Test (Dry
Products/Tablets) X X X X
Stability X X X X
TOXICOLOGY
In-Vitro Cytotoxicity X X X X
Acute Ocular Irritation X X X X
Acute Oral Toxicity X
Sensitization X
In-Vivo Ocular Biocompatibility X
CLINICAL
Recommended Size/Scope of Clinical
Study
30 subj/1 mo FOOTNOTE B 60 subj/3 mo
FOOTNOTE A: If the spent solution has a pH of 7.2 + 0.2 and tonicity of 290-320 mOsm/kg, manufacturers are not required, in most instances, to submit
compatibility data.
FOOTNOTE B: Clinical performance data may need to be submitted depending on the physical/chemical, microbiological and toxicological data collected. If
necessary, a 30 subject/1 month clinical study should be conducted.

` 35
TESTING MATRIX FOR CONDITIONING SOLUTIONS	TESTING MATRIX FOR CONDITIONING SOLUTIONS
Same Active Ingredients
Within Marketed
Concentrations
Same Active Ingredients In
Higher Concentrations Than
Marketed Products
Same Active Ingredients In
Lower Concentrations Than
Marketed Products
New Ingredients for
Ophthalmic Use or
Different Active
Ingredient
CHEMISTRY
Stability X X X X
Solution Compatibility FOOTNOTE A FOOTNOTE A FOOTNOTE A X
Wetting Angle X X X X
MICROBIOLOGY
Sterility X X X X
Preservative Effectiveness with
Rechallenge X X X X
Disinfection Efficacy X X X X
Stability X X X X
TOXICOLOGY
In-Vitro Cytotoxicity X X X X
Acute Ocular Irritation X X X X
Acute Oral Toxicity X
Sensitization X
In-Vivo Ocular Biocompatibility X
CLINICAL
Recommended Size/Scope of Clinical
Study
30 subj/1 mo 60 subj/3 mo
FOOTNOTE A: If the conditioning solution has a pH of 6.6-7.8 and tonicity of 290-320 mOsm/kg, manufacturers are not required, in most instances, to
submit compatibility data.

` 36
Chemistry:
In addition to the information listed in Section II (General Manufacturing
Information) and as outlined in the testing matrices in this section, the
following should be provided, when appropriate:
For conditioning solutions:
1. wetting angle of hydrophobic lenses in conditioning solution as a
function of soaking time; and
2. the pH, tonicity and viscosity of the conditioning solution.
For chemical disinfection solutions:
pH and tonicity of the chemical disinfection solution used for
hydrophilic contact lenses.
For H2O2 systems:
1. the pH and tonicity for the H2O2 and neutralization solutions;
2. the pH, tonicity and residual H2O2 of the spent solution following
neutralization for a H2O2 disinfecting system;
3. for neutralization solution, tablets, or disks, a neutralization
profile under the recommended care regimen should be provided:
a. if a disk is used, manufacturers should establish a discard
date based upon the maximum number of effective uses of the
neutralization disk; and
b. if a time-delayed tablet is used for a
disinfecting/neutralization system, the following additional
information is needed:
(1) materials for coating the tablet (e.g., nature of
polymer, average molecular weight, molecular weight
distribution, and swelling); and
(2) QA/QC procedures and sampling plan for time-delayed
release tablet.
Microbiology:
See Section II (General Manufacturing Information), the applicable testing
matrices for Soaking Solutions for Disinfection, Neutralizing Solutions, and
Conditioning Solutions, and Section VI (Recommended Test Methods) Micro--
Appendices A-B for guidance on recommended microbiology tests for including in
the 510(k).
The disinfection efficacy of a disinfecting solution, system, or a
conditioning solution should be evaluated by the stand-alone procedure [see
Section VI (Recommended Test Methods) Micro--Appendix B, Part 1]. If the

` 37
product does not meet the primary criteria, but does meet the secondary
criteria, the product should then be evaluated by the regimen procedure
(Micro--Appendix B, Part 2).
Toxicology:
See Testing Matrices for Soaking Solutions for Disinfection, Neutralizing
Solutions, and Conditioning Solutions and Section VI (Recommended Test
Methods) Tox--Appendices A-B.
For H2O2 disinfection systems, toxicology testing should be performed on the
neutralized disinfection solution (i.e., spent solution).
Clinical:
See applicable Testing Matrices for Soaking Solutions for Disinfection,
Neutralizing Solutions, and Conditioning Solutions for guidance on recommended
size and scope of clinical trials. Further guidance on protocol development
is available in Section VI (Recommended Test Methods) Clin--Appendices A-E.

` 38
D. MULTI-PURPOSE SOLUTION
A multi-purpose solution is generally defined as a single contact lens
care solution that contains multiple active ingredients in sufficient
concentrations to perform the functions of daily cleaning, chemical
disinfection, rinsing and storage of contact lenses. Because of the
multiple uses claimed for this individual solution, information should
be submitted in a 510(k) to support all claims identified in the
labeling. In addition, strict attention should be paid to the labeling
for this product to assure that adequate directions for use (e.g.,
rubbing and rinsing times for daily cleaning, soak times for
disinfection, and maximum storage times following disinfection) are
provided for all intended uses identified above.
A contact lens solution that cannot perform all of the functions
identified above should not be labeled as a multi-purpose contact lens
care solution [see Labeling section for multi-purpose solutions below
and Section V (Labeling) for further guidance on labeling for multi-
purpose contact lens solutions].
Chemistry:
See applicable testing matrices and Section VI (Recommended Test
Methods) for the recommended manufacturing/chemistry tests for the
applicable indications (e.g., daily cleaning and disinfection
solutions).
Microbiology:
See Section II (General Manufacturing Information), applicable testing
matrices, and Section VI (Recommended Test Methods) for the recommended
microbiology tests for the applicable indications (e.g., daily cleaning
and disinfection solutions).
Toxicology:
See applicable testing matrices and Section VI (Recommended Test
Methods) for the recommended toxicology tests for the applicable
indications (e.g., daily cleaning and disinfection solutions).
Clinical:
See applicable testing matrices for guidance on size and scope of a
clinical trial for the applicable indications (e.g., daily cleaning and
disinfection solutions). Further clinical guidance on protocol
development is available in the Section VI (Recommended Test Methods)
Clin--Appendices A-E.
Labeling:
Policy for Multi-Purpose Solutions:
Applicants are advised that a multi-purpose solution should not be
labeled as an ALL-IN-ONE solution. CDRH believes that an ALL-IN-
ONE claim can be misleading for these products because lubricating

` 39
and rewetting drops as well as enzyme treatment are utilized for
complete lens care.
Multi-purpose products are usually labeled for cleaning and
disinfecting. It is potentially unsafe to label a product
intended for cleaning and disinfecting for in-eye use as well
since consumers may inappropriately use other cleaners and
disinfecting solutions that are not compatible with in-eye use. A
multi-purpose solution should not be labeled for lubricating and
rewetting lenses during wear even if the chemical compositions of
the multi-purpose solution and lubricating and rewetting drops are
identical.
CDRH maintains a working policy that lubricating and rewetting
drops should be packaged in bottle sizes not to exceed 30 ml in
order to minimize the risks of contamination and possible eye
infections and facilitate ease of use.
Therefore, based on concerns for contamination during use and
consumer misuse and confusion, it is CDRH's policy to discourage
manufacturers from labeling multi-purpose solutions for in-eye
indications for use. CDRH believes that a policy of limiting
indications for in-eye use solutions to that single intended use
enhances product safety and encourages consumer compliance with
safe lens care practices.
See Section V (Labeling) for general guidance for developing labeling
for contact lens care products. In addition, predicate device labeling
should also be used as general guidance for labeling new multi-purpose
solutions.

` 40
E. IN-EYE CONTACT LENS SOLUTIONS (Lubricating and/or Rewetting Drops)
An in-eye solution for use with contact lenses (e.g., lubricating and/or
rewetting drops) is generally defined as a contact lens care solution
containing one or more active ingredients (e.g., ophthalmic demulcents)
in sufficient concentration to alleviate symptoms of discomfort from
contact lens wear by a physical means as opposed to a pharmacological
action generally associated with OTC in-eye solutions regulated as
drugs. A preparation labeled for use with contact lenses which contains
an ophthalmic demulcent, as listed in 21 CFR 349.12, will qualify as a
lubricating drop based on formulation. All predicate lubricants to date
contain a demulcent. If a preparation does not contain a demulcent
(e.g., a small volume unit-dose saline), it would qualify as a rewetting
drop, not as a lubricating drop. Predicate device labeling should be
used as a comparison for intended use.
The devices in this category of products, generally referred to as
lubricating and/or rewetting lens drops, are intended for direct
instillation in the eye while wearing contact lenses to achieve the
intended purpose. These products may also be used to lubricate and/or
rewet lenses prior to insertion in the eye.
Policy for Multi-Dose In-Eye Contact Lens Solutions:
CDRH believes that lubricating and rewetting drops should be
packaged in bottle sizes not to exceed 30 ml in order to minimize
the risks of contamination and possible eye infections and
facilitate ease of use. The risk of contamination with multi-dose
in-eye contact lens solutions should be further minimized by
formulating the product to contain one or more suitable harmless
substances such as a preservative, that will inhibit the growth of
microorganisms. Alternatively, in-eye contact lens solutions may
be packaged as to volume and type of container and appropriately
labeled to afford adequate protection and minimize the hazard of
injury resulting from contamination during use (e.g., unpreserved
in unit-dose containers).
CDRH recognizes that a solution manufacturer that produces a
product with an identical formulation to that of an in-eye lens
solution, such as a saline or conditioning solution, which is
marketed in a size larger than 30 ml will be discouraged by this
policy from labeling the solution for in-eye use. Also, the
Policy for Multi-Purpose Contact Lens Solutions (see Section
III D, Multi-Purpose Solution) would discourage labeling certain
products for in-eye use indications.
In addition, it is encouraged that labeling for multi-dose in-eye
contact lens solutions include instructions to discard the
solution after a specified period after opening. If a discard
date is proposed, it should be based on the package size,
projected number of uses, and frequency of use.
CDRH believes that a policy of limiting indications for in-eye use
solutions to that single intended use enhances product safety and
encourages consumer compliance with safe lens care practices.

` 41
TESTING MATRIX FOR IN-EYE CONTACT LENS PRODUCTS	TESTING MATRIX FOR IN-EYE CONTACT LENS PRODUCTS
Same Active Ingredients
Within Marketed
Concentrations
Same Active Ingredients In
Higher Concentrations Than
Marketed Products
Same Active Ingredients In
Lower Concentrations Than
Marketed Products
New Ingredients for
Ophthalmic Use or
Different Active
Ingredient
CHEMISTRY
Stability X X X X
Solution Compatibility FOOTNOTE A FOOTNOTE A FOOTNOTE A X
MICROBIOLOGY
Sterility X X X X
Preservative Effectiveness with
Rechallenge X X X X
Stability X X X X
TOXICOLOGY
In-Vitro Cytotoxicity X X X X
Acute Ocular Irritation X X X X
Acute Oral Toxicity X
Sensitization X
In-Vivo Ocular Biocompatibility X
CLINICAL
Recommended Size/Scope of Clinical
Study
30 subj/1 mo 30 subj/1 mo 30 subj/1 mo 60 subj/3 mo
FOOTNOTE A: If the in-eye contact lens solution has a pH of 6.6-7.8 and tonicity of 290-320 mOsm/kg, manufacturers are not required, in most instances,
to submit compatibility data.

` 42
Chemistry:
See Section II (General Manufacturing Information) Testing Matrix for In-Eye
Contact Lens Solutions, and Section VI (Recommended Test Methods) Chem--
Appendices A and C, for guidance on recommended tests for including in a
510(k).
In addition, for lubricating solutions, manufacturers should identify and
characterize the ophthalmic demulcent as listed in 21 CFR 349.12 and provide
pH, tonicity, and viscosity.
Microbiology:
See Section II (General Manufacturing Information), Testing Matrix for In-Eye
Solutions, and Section VI (Recommended Test Methods) Micro--Appendices A-B,
for guidance on recommended tests for including in a 510(k).
Toxicology:
See Testing Matrix for In-Eye Solutions and Section VI (Recommended Test
Methods) Tox--Appendices A-B, for guidance on recommended tests for including
in a 510(k).
Clinical:
See Testing Matrix for In-Eye Solutions for guidance on size and scope of a
clinical trial. Further clinical guidance on protocol development is
available in Section VI (Recommended Test Methods) Clin--Appendices A-E.
Applicants are reminded that FDA generally considers clinical studies of
certain solutions intended to be used directly in the eye to be significant
risk investigations which require both IRB and FDA review and approval prior
to initiating clinical studies. Applicants should refer to the "Introduction"
section for guidance concerning significant risk clinical studies.

` 43
F. HEAT DISINFECTION UNITS
A heat disinfection unit is a contact lens care product intended to
disinfect soft (hydrophilic) contact lenses by means of heat. Heat
disinfection units act by transferring sufficient heat to a contact lens
case containing the lenses and saline solution for a specified period of
time to destroy harmful microorganisms on the lenses.
Manufacturing/Chemistry:
The following manufacturing/chemistry guidance should be used when
submitting a 510(k) for a heat disinfection unit:
A positive function/failure indicator should be installed in the heat
unit circuitry. Any 510(k) for a heat unit without a positive
function/failure indicator should have an acceptable justification for
not having the indicator. A positive function/failure indicator is one
that:
• indicates that the unit is heating or on only when heat is being
generated or electrical current is flowing through the heat
element; and
• indicates that the unit is cool or off only when the temperature
has dropped towards room temperature or when no current is flowing
in the heat unit.
Units that meet this definition would include:
• electrically timed or thermostatically controlled units in which a
light emitting indicator is effectively in series with the heater;
and
• units that use a temperature sensing element that changes color or
provides a similar distinct indication between room temperature
and elevated temperature.
A 510(k) for a heat disinfection unit should contain:
1. time-temperature curves from a statistically significant sample of
units which demonstrate that the lower three standard deviation
points of the distribution of time-temperature curves is greater
than the minimum time-temperature necessary for effective heat
disinfection;
2. electric circuitry and safety features;
3. certification that the heat disinfection unit conforms to the
requirements of applicable electrical safety standards [e.g.,
Underwriters Laboratories (UL) 1431 entitled "Personal Hygiene and
Health Care Appliances"].
4. QA/QC procedures and sampling techniques (e.g., Military
Standard 105E) for critical components;

` 44
5. QA/QC procedures and sampling techniques (e.g., Military
Standard 105E) for final device; and
6. 30-cycle lens compatibility under the recommended care regimen.
Microbiology:
Microbiology data are generally not required for heat disinfection units
provided the heat disinfection cycle time and temperature are equivalent
to those of the predicate device (e.g., 80oC for 10 minutes).
If an alternative heat disinfection cycle is proposed, microbicidal
efficacy should be demonstrated by a microbial challenge test utilizing
at least 10 units and 20 lenses each from lens groups I and IV. The
following procedure is recommended:
Inoculate lenses with approximately 1 X 106 organisms Enterococcus
faecalis (formerly Streptococcus faecalis) (recommended strain:
Ward's Natural Science Establishment #85 W 1100) in organic soil,
and expose to the proposed heat disinfection cycle. Prepare the
organic soil inoculum as described in Section VI (Recommended Test
Methods) Micro--Appendix B, Part 2:III.B and an inoculum control
as described in Micro--Appendix B, Part 2:D.1. After heat
disinfection, culture lenses as described in Micro-Appendix B,
Part 2:III.C.3. If a preserved saline is used in the heat
disinfection process, use a recovery medium that contains one or
more neutralizing agents. Validate the recovery medium as
described in Micro--Appendix B, Part 2:D.2.
All lens and test filter combinations should show no growth.
Toxicology:
Toxicology data are generally not required for heat disinfection units
provided the heat disinfection unit is essentially identical to the
predicate device unless the heat unit is also designed for use as a lens
case. In the latter situation, toxicology information similar to that
for lens cases should be provided.
Clinical:
Clinical data are not generally required for heat disinfection units
provided the specifications for the heat disinfection unit are
substantially equivalent to the predicate device.

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G. CONTACT LENS CASES
A contact lens case is a lens care product to be used by the contact
lens wearer or practitioner for storing contact lenses while not being
worn. Contact lens cases are especially designed for use in chemical,
heat or H2O2 disinfecting systems. Not included in this definition are
lens cases intended by the manufacturer only for shipping the lenses in
a dry state.
Manufacturing/Chemistry:
The following manufacturing/chemistry information should be provided in
the 510(k):
1. Engineering drawing and a brief description of polymeric materials
used.
2. Physical and chemical data of polymeric materials used and name
and address of the manufacturer.
3. If the lens case is used in heat disinfection, the applicant
should provide proof that the lens case can withstand repeated
heat disinfection. Physical and chemical data of polymeric
material (e.g., heat distortion temperature or glass transition
temperature may be used to substantiate this indication). In
general, a lens case used in heat disinfection should contain a
rubber gasket.
4. The volume capacity of the lens case (e.g., should be of
sufficient volume to assure that the lens remains completely
immersed under conditions of use).
5. Certification that colorants used in the manufacture of the lens
case are insoluble in water [this information is often found in
the material safety data sheet (MSDS)].
Microbiology:
Microbiology testing requirements for lens cases are dependent upon
claims made in the labeling. In general, microbiology issues pertaining
to contact lens cases are covered by the warning recommended in the
labeling [see Section V (Labeling)].
Toxicology:
Toxicology data from the following tests conducted on both the plastic
and gasket materials should be provided:
1. Systemic Toxicity Test (see USP/NF XXII for methodology)
2. Acute Ocular Irritation Test
3. In-Vitro Cytotoxicity Test

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See Section VI (Recommended Test Methods) Tox--Appendices A-B for
guidance.
CDRH is aware that suppliers of plastic and other materials generally
provide MSDSs to manufacturers of devices using their materials.
Manufacturers are encouraged to carefully scrutinize the information
provided in these MSDSs to determine if they contain the needed
toxicology information before initiating the recommended tests. If the
information is included on the MSDS, the MSDS may be provided in lieu of
toxicology data. MSDSs should be provided in 510(k)s.
Clinical:
Clinical data are generally not required to be submitted in a 510(k) for
lens cases. However, manufacturers should consider the impact of
design, materials and intended use on need for clinical performance
data.

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H. CONTACT LENS ACCESSORIES (e.g., Mechanical Cleaning Aids and Accessory
Cleaning Pads)
Contact lens accessories (e.g., mechanical cleaning aids and accessory
cleaning pads) are devices used as cleaning aids in conjunction with
contact lens cleaning solutions.
1. Mechanical Cleaning Aid: A mechanical cleaning aid may be
available as a hand or battery-operated or electrical device that
aids in cleaning contact lenses by generating ultrasound, tumbling
motions, or vibrations for the cleaning solution while it cleans.
It may also act as a receptacle during the rinsing or chemical
disinfecting steps in the lens care regimen.
Although the mechanical cleaning aid has not been officially
classified, in the past CDRH has evaluated requests for marketing
such devices through the 510(k) process. With the availability of
this special controls document, it is our present intention to
allow manufacturers of SE mechanical cleaning aids to label their
devices for use as accessories to approved contact lens cleaning
solutions.
Applicants are advised that if the new device contains a new
technology, performance data (e.g., cleaning effectiveness) may be
required to demonstrate substantial equivalence. DOD should be
contacted concerning protocol development for performance data for
510(k)s for devices containing new technology (telephone number at
the end of Introduction section).
Manufacturing/Chemistry:
The following information should be provided in the 510(k) for the
mechanical cleaning aids (as applicable):
a. a detailed description of the device and engineering
drawings;
b. a mode of action (e.g., ultrasound);
c. electric circuitry and safety features if applicable [e.g.,
for all electrical devices, certification that they conform
to the requirements of applicable electrical safety
standards (e.g., UL 1431 entitled, "Personal Hygiene and
Health Care Appliances")]; and
d. if the device generates heat when used according to the
directions in the labeling, an assessment of this affect on
the lens parameters and durability.

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Microbiology:
Microbiology testing requirements for mechanical cleaning aids are
dependent upon claims made in the labeling. In general,
sufficient microbiology data should be submitted to support all
claims being made in the labeling.
Toxicology:
Toxicology data from the following tests conducted on the
materials (e.g., gaskets, plastics, etc.) that come in contact
with the solutions should be provided:
a. Systemic Toxicity Test (see USP/NF XXII for methodology)
b. Acute Ocular Irritation Test
c. In-Vitro Cytotoxicity Test
See Section VI (Recommended Test Methods) Tox--Appendices A-B for
guidance.
CDRH is aware that suppliers of plastic and other materials
generally provide MSDSs to manufacturers of devices using their
materials. Manufacturers are encouraged to carefully scrutinize
the information provided in these MSDSs to determine if they
contain the needed toxicology information before initiating the
recommended tests. If the information is included on the MSDS,
the MSDS may be provided in lieu of toxicology data. MSDSs should
be provided in 510(k)s.
Clinical:
Clinical data are generally not required to be submitted in a
510(k) for mechanical cleaning aids. However, manufacturers
should consider the impact of design, materials and intended use
on need for clinical performance data in order to provide adequate
directions for use of the device.
2. Accessory Cleaning Pads: Accessory cleaning pads are made of
materials that generally contain mildly abrasive surfaces. The
pads are intended to be used in conjunction with contact lens
cleaning solutions to aid in lens cleaning by minimizing direct
contact with the hands.
Manufacturing/Chemistry:
The following manufacturing/chemistry information should be
provided in the 510(k):
a. compatibility data that demonstrate the cleaning pad will
not damage (e.g., scratch) the lenses; and
b. a detailed description of the chemical components of the
device.

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Microbiology:
The applicant should identify and provide information to address
all potential microbial concerns raised by reuse of the pad, if
the pads are to be reused, in which case cleaning instructions for
the pad should be provided. In addition, appropriate lens
cleaning instructions, warnings, and precautions should be
included in the labeling.
Toxicology:
The following toxicology information should be provided in the
510(k):
Data demonstrating that any materials coming in contact with
the cleaning solutions are not eye irritants. This
information may be provided in an MSDS or from testing
conducted in accordance with the Acute Ocular Irritation
Test found in Section VI (Recommended Test Methods) Tox--
Appendix-A.
Clinical:
Clinical data are not generally required to be submitted in a
510(k) for accessory cleaning pads. However, manufacturers should
consider the impact of design, materials and intended use on need
for clinical performance data.

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IV. MODIFICATIONS OF APPROVED CONTACT LENS CARE PRODUCTS REQUIRING A 510(k):
A. A manufacturer with a PMA or a 510(k) for a contact lens care
product may, for a variety of reasons, want to modify the device.
Based on our knowledge and experience with contact lens care
products, CDRH has listed the following changes to approved care
products that could significantly affect safety and effectiveness
of the device and thus require 510(k) clearance under 21 CFR
807.81(a). These changes include, but are not necessarily limited
to, the following:
1. a change in an active ingredient or concentration of the
active ingredient;
NOTE: Although this guidance document focuses primarily on
active ingredients, manufacturers should also assess the
effects of inactive ingredients (e.g., buffering agents and
tablet coatings) on such factors as pH, tonicity,
preservative effectiveness, solution compatibility with
lenses, and preservative uptake/release to determine if the
change significantly affects safety and effectiveness of the
device and, therefore, requires submission of a 510(k).
2. addition of a new ingredient for ophthalmic use;
3. a change in preservative or preservative concentration in
solutions;
4. a major change or modification in the product specific
intended use of the device or indication for use (e.g.,
addition of performance information in the labeling that
implies that the device can be used for previously
unmentioned product specific use such as adding a cleaning
claim to a disinfecting solution to create a multi-purpose
solution or claiming that the device can be used for a
different type of lens such as hydrophobic when previously
hydrophilic was indicated);
5. changes in the directions for use affecting product
performance (e.g., decreased soak times for disinfecting
solutions or periodic cleaners);
6. a change in the type of container/closure and delivery
systems of a contact lens solution [e.g., changing from a
plastic bottle to an aerosol can or changing from a chemical
preservative system to a physical barrier (e.g., filters)
preservative system for contact lens solution];
7. changes in dosage form (e.g., adding tablet coatings for
time release or changing from a liquid to tablet preparation
of the active agents); and

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8. addition or deletion of a contraindication:
NOTE: Manufacturers should submit a Special 510(k)--Changes
Being Effected to add a contraindication. Applicants should
refer to existing FDA policy for guidance on deciding when
to submit a 510(k) for a labeling change to an existing
device. Deletion of a contraindication would be expected to
change the intended use and would, therefore, require
submission of a new 510(k).
B. Listed below are some examples of changes that should not require
a 510(k) to be submitted provided the change adheres to current
FDA policies and is adequately documented:
1. addition of private label distributors who are not
manufacturing the product;
2. extension of the expiration date according to a
cleared/approved protocol;
3. a change to a smaller or larger size container made from
identical materials provided stability studies are done
according to a cleared/approved protocol and product
specifications remain unchanged. If the new container is no
more than 8 times larger than the smallest size container
for which stability/sterility testing data have previously
been evaluated, no additional stability studies are
necessary. In accordance with 21 CFR 800.10(b), contact
lens solutions should be so packaged as to volume and type
of container to minimize contamination during use. The
largest size product container currently marketed is a 16
fl. oz size. [See Section VI (Recommended Test Methods,
Shelf-Life Protocol) in the Appendices];
4. changes in packaging material (e.g., high density
polyethylene to low density polyethylene) provided: (1) the
new materials meet USP requirements (Containers for
Ophthalmics Plastics--Biological Test Procedures) and
leachables do not cause eye irritation, (2) the new
materials do not compromise sterility package integrity, and
(3) shelf-life is re-established according to a
cleared/approved protocol.
5. changes in container shapes;
6. changes in trade name provided the new trade name does not
misbrand the device;
7. adding a new manufacturing site without changing the
manufacturing processes;
8. reformatting or editorial changes in labeling;

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9. changes from one traditional sterilization method utilized
for the sterilization of the final product, raw materials or
packaging materials to another traditional method (e.g.,
from ETO to gamma radiation) provided: (1) the new method
meets an acceptable SAL (10-6 for terminal sterilization and
10-3 for aseptic processing) and does not change the product
performance specifications and (2) shelf-life is re-
established according to a cleared/approved protocol;
10. documented changes in manufacturing process that could not
significantly affect the safety or effectiveness of the
device and are implemented in accordance with GMP
requirements; and
11. adding or strengthening precautions or warnings in
accordance with existing FDA policy.
NOTE: Manufacturers should monitor device usage and
periodically revise their warnings and precautions sections
based on use experience. A 510(k) for such a change in
precautions or warnings generally does not require
submission of a 510(k) unless the change results in a new
intended use. However, manufacturers should document these
changes in their files.
If after reviewing the above changes specifically identified in this
product specific guidance document as needing a new 510(k), applicants
are unable to determine whether a 510(k) is required for a proposed
modification to a contact lens care product, they may consult existing
FDA policy (e.g., Blue Book Memorandums) on modifications needing a
510(k).

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V. LABELING
TABLE OF CONTENTS
Page
Introduction................................................................54
Labeling Examples:
1. Pre-Formulated Solutions and Tablets (Appendix A)...............57
2. Lens Cases (Appendix B).........................................71
3. Heat Disinfection Units (Appendix C)............................72
4. Salt Tablets/Capsules (Appendix D)..............................76
5. Contact Lens Accessories Such as
Mechanical Cleaning Aids (Appendix E).....................78
Accessory Cleaning Pads (Appendix F)......................79

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V. LABELING
A. Introduction:
This section of the guidance provides general information on the
applicable regulations and requirements for labeling of contact lens
care products, what information should be submitted for review of a
510(k) for these devices, and guidance on preparing labeling for contact
lens care products [e.g., contact lens solutions and tablets, lens
cases, heat disinfection units, salt tablets/capsules, and contact lens
accessories (e.g., mechanical cleaning aids and accessory cleaning
pads)] respectively.
Contact lens care products are subject to the general labeling
requirements for all medical devices outlined in 21 CFR 801. Contact
lens solutions are further subject to 21 CFR 800.10, Contact Lens
Solutions; Sterility and 21 CFR 800.12, Contact Lens Solutions and
Tablets; Tamper-resistant Packaging.
CDRH considers adequate labeling to be an important safeguard (special
control) for assuring that new contact lens care products are
substantially equivalent in terms of safety and effectiveness to legally
marketed devices. Applicants are encouraged to provide predicate device
labeling in their 510(k) submissions.
B. Labeling Information Required in an Original 510(k) or 510(k) for a
Modification:
Under 21 CFR 807.87(e), a 510(k) applicant is required to submit
proposed labels, labeling, and advertisements sufficient to describe the
device (composition), its intended use (i.e., indications for use), and
the directions for its use. This basic information is required before
CDRH can render a substantial equivalence determination for either an
original 510(k) or for a 510(k) that includes modifications (e.g.,
changes in device description, intended use, or directions for use) if
the modification significantly affects safety or effectiveness of the
device. In addition, manufacturers should submit a 510(k) before making
a change such as adding or deleting a contraindication (see Section IV).
C. Regulatory Guidance:
Information that generally accompanies the sale and distribution of
contact lens care products can include, but is not limited to, such
printed matter as outer carton labeling, bottle or device label, and
(for solutions) a package insert. CDRH considers such printed matter to
be labeling as described in Section 201(m) of the act, which also
provides general guidance as to the type of information that should be
included in contact lens care product labeling. Because labeling is not
approved when 510(k) clearance is granted, the manufacturer should be
advised that once the device is marketed, the device is required to be
labeled in accordance with applicable regulations which include, among
other things, prohibition against misbranding and including false and
misleading information in the labeling. In order to avoid violating the
labeling regulations, applicants should scrutinize their labeling in

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draft for words or phrases that are exaggerated, potentially ambiguous,
or subjective as well as unsubstantiated statements, claims, or puffery.
Such words or phrases in labeling may be considered false or misleading,
and if marketed with false or misleading claims, could cause the
manufacturer to be subject to regulatory action. CDRH urges applicants
to carefully adhere to pertinent labeling regulations and DO NOT PRINT
LABELING IN FINAL FORM until a substantial equivalency letter is
received.
Pertinent Labeling Regulations:
• Definitions of "label" and "labeling" [Sections 201(k) and 201(m)
of the act].
• Information required in a premarket notification submission
pertaining to labeling (21 CFR 807.87(e)).
• General Labeling Provisions (21 CFR 80l); Contact Lens Solutions;
Sterility (21 CFR 800.10); and Contact Lens Solutions and Tablets;
Tamper-resistant Packaging (21 CFR 800.12).
• Explanation of what causes a device to be misbranded and false and
misleading labeling (Section 502 of the Act, 21 CFR 80l.6, 807.39,
and 807.97).
The following references or their most recent revisions may be consulted for
further guidance:
1. Labeling Regulatory Requirements for Medical Devices. This
publication discusses such areas as advertising material
considered labeling, what is false and misleading labeling,
adequate directions for use, and provides examples of ways that
device manufacturers can comply with labeling requirements.
Copies of this publication can be obtained by contacting DSMA (fax
and telephone numbers are at the end of the Introduction section).
2. Device Labeling Guidance #G91-1 (Office of Device Evaluation Blue
Book Memorandum). This guidance provides detailed interpretations
of applicable labeling regulations, and can be obtained from DSMA
(fax and telephone numbers are at the end of the Introduction
section).
3. Human Factors Principles of Medical Device Labeling. This
guidance pertains to labeling for all medical devices. It
contains basic principles for the effective design of instruction
booklets for medical device use. Along with the principles are
selected examples (graphics, cleaning steps, etc.) abstracted from
a generic model booklet. These examples do not contain all
elements required by 21 CFR 80l, but they embody human factors
principles and may be used, along with predicate labeling, as a
guide in writing your labeling. This guidance is available by
contacting DSMA (fax and telephone numbers are at the end of the
Introduction section).

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D. Labeling Examples:
An outline and specific device information that should be included in
pre-formulated solution and tablet labeling based upon predicate device
labeling is provided in Labeling--Appendix A.
Labeling--Appendix A also includes an example of a package insert for
aerosol saline solution that incorporates principles taken from labeling
entitled, "Improved Patient Instructions for Care of Soft Contact
Lenses," that was prepared by a CDRH focus group based upon a study
using consumers and Write-It-Right principles (Write-It-Right booklet is
available by contacting DSMA (fax and telephone numbers are at the end
of the Introduction section).
Applicants are advised that although it is not required that they use
the exact wording in the product specific contraindications, warnings,
precautions, etc., provided in this outline, FDA recommends the basic
content not be changed. Thus, to avoid the potential for changes in
meaning, we encourage applicants to exercise care.
An applicant may follow the format using Write-It-Right principles or
follow the format in the most recently marketed predicate device
labeling.
In cases where individual devices require unique warnings, precautions,
contraindications, etc., in addition to those recommended in the
specific device information sections, applicants should provide
sufficient information in the 510(k) to support the inclusion of these
unique statements in their labeling.
Labeling--Appendices B-F contain examples of labeling for lens cases,
heat disinfecting units, salt tablets/capsules systems, and contact lens
accessories (e.g., mechanical cleaning aids and accessory cleaning
pads), respectively.
If further labeling guidance is required, applicants may contact DOD
(fax and telephone numbers are at the end of the Introduction section).

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LABELING--APPENDIX A
Package Insert for Pre-Formulated Solutions and Tablets
Labeling--Appendix A includes (1) an outline and specific device information
that should be included in a package insert for pre-formulated solutions and
tablets, (2) an outline of specific device information that should be included
on the outer carton and bottle labeling for these devices, and (3) an example
of a package insert for aerosol saline using Write-It-Right principles.
In preparing labeling, applicants should fill in the brackets by including
specific information pertaining to the device in the 510(k). Predicate device
labeling, the outline below, and the example provided in this section may be
used as further guidance.
SAMPLE PACKAGE INSERT
PLEASE READ CAREFULLY AND KEEP THIS PACKAGE INSERT FOR FUTURE USE.
DESCRIPTION:
[Include "sterile" if it is a solution; list active ingredients and quantitate
the preservative(s) 00.0%] [optional, list inactive ingredients]. When
applicable, include the following additional descriptive information:
isotonic
buffered
preserved/unpreserved
propellants
enzyme
tablet, disk, or [describe]]
ACTIONS:
[Include a concise description of the function of the device (i.e., how the
device works in relation to the contact lens). When applicable, the actions
may be listed with the indications (i.e., INDICATIONS/ACTIONS)].
INDICATIONS (USES):
[Include a description of the proper use of the device. NOTE: The
indications should be essentially the same as the predicate device.]
CONTRAINDICATIONS:
Contraindications describe situations in which the device should not be used
because the risk of use clearly outweighs any possible benefit. If there are
no contraindications, include the statement: "There are no known
contraindications for use of this product." Include all contraindications
specific to your device. Listed below is a general contraindication.

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For all contact lens pre-formulated solutions:
• If you are allergic to any ingredient in this product, DO
NOT use.
• Add additional contraindications if applicable to specific
device.
WARNINGS:
Warnings include serious adverse reactions and potential safety hazards,
limitations in use imposed by them, and steps that should be taken if they
occur. Listed below are (1) general warnings that pertain to all pre-
formulated solutions and tablets and (2) product specific warnings. Include
those general and specific warnings that apply to the device in the 510(k).
General Warnings:
• To avoid contamination, DO NOT touch tip of container to any
surface. Replace cap after using.
• To avoid contaminating your solution, DO NOT transfer to other
bottles or containers.
• Add additional warnings if applicable to specific device.
Product Specific Warnings:
Saline Solutions: Add the following specific warnings following heat
disinfection (when applicable):
• To minimize the risk of contamination, keep lenses in the unopened
case until ready to wear.
1. Aerosol Salines
• Contents under pressure, DO NOT spray directly into the eye
as serious injury to the eye may result.
• DO NOT puncture or incinerate can.
• DO NOT store at temperature above 120oF.
• Always spray a small amount of solution into the sink to
clear the nozzle of contaminants before spraying the saline
onto your lenses.
2. Unpreserved Saline
• To minimize the risk of eye infection DO NOT use this
solution beyond the recommended discard date.

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3. Unit Dose Saline
• This product is provided in a single dose package that does
not contain preservatives. To minimize the risk of
contamination and possible eye infection, DO NOT save and
reuse any unused saline. Discard the package immediately
after use.
Daily Cleaners:
• DO NOT use directly in the eye. Solution may cause severe
irritation, burning and stinging.
Periodic Cleaners:
• DO NOT dissolve enzyme tablets in distilled or tap water.
Distilled water and tap water are non-sterile. Use of non-
sterile products may lead to microbial contamination of
lenses which can cause serious eye infections.
• After cleaning with enzyme cleaner, your lenses should be
cleaned with a daily cleaner, rinsed and disinfected.
Failure to do so may result in eye irritation, burning, or
stinging.
• DO NOT put solution directly in the eye as severe
irritation, burning and stinging may result.
Chemical Disinfecting Solutions/Systems and Conditioning Solution:
NOTE: No individual product within a chemical disinfection regimen
should be labeled as the "disinfecting solution" unless it can meet the
primary criteria of the stand-alone microbiology disinfection test (as
referenced in Section VI, Recommended Test Methods, Micro--Appendix B
Part 1). Chemical disinfection regimens which meet the regimen
procedure criteria may be labeled, for example, as having a starting
solution and a finishing solution or as having a cleaning solution and a
soaking solution, but no individual product should be labeled as the
disinfecting solution.
• DO NOT use with heat (thermal) disinfection unless
specifically indicated in labeling.
Warnings for Hydrogen Peroxide Disinfecting Solutions:
• KEEP [TN] disinfecting solution (hydrogen peroxide) OUT OF
THE EYES. ALWAYS USE [TN] (neutralizer) with [TN]
disinfecting solution to NEUTRALIZE YOUR LENSES BEFORE
APPLYING THEM TO YOUR EYES. If [TN] disinfecting solution
accidentally comes in contact with the eyes, it may cause
burning, stinging or redness. Remove your lens(es)
immediately and flush your eyes with a large amount of water
or sterile saline. If burning or irritation continues, seek
professional assistance.

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• Keep [TN] disinfecting solution (hydrogen peroxide) out of
the reach of children. If accidentally swallowed, an upset
stomach and vomiting may result. Seek immediate
professional medical assistance or contact a poison control
center.
• Not for use with heat (thermal) disinfection because [state
reason].
Warnings for Neutralizing Products (when applicable):
• This tablet is not to be taken internally. If accidentally
swallowed, an upset stomach and vomiting may result. Seek
immediate professional medical assistance or contact a
poison control center.
• DO NOT crush the [TN] Neutralizing Tablet. If a crack
occurs in the coating, the tablet may begin to neutralize
the [TN] Disinfecting Solution before adequate disinfection
occurs.
• DO NOT use [TN] Neutralizer disk for more than XXX uses or
XX months of daily use. [Note: Uses and time period to be
determined by testing data.]
Warnings for Conditioning Solutions:
• DO NOT use with soft (hydrophilic) contact lenses. Soft
(hydrophilic) contact lenses can absorb solution components
that may cause severe irritation, burning and stinging of
the eyes.
In-Eye Contact Lens Solutions:
• To minimize the risk of contamination and eye infection, DO
NOT use beyond the discard date on the bottle label (if
applicable).
The following non-product specific warnings have been included in
predicate device labeling (as applicable) as a "public service"
announcement:
Warnings for Hydrophilic Contact Lens Products:
Warnings: PROBLEMS WITH CONTACT LENSES AND LENS CARE PRODUCTS
COULD RESULT IN SERIOUS INJURY TO THE EYE. Follow your eye care
practitioner's directions and all labeling instructions for proper
use and care of your lenses and lens care products, including the
lens case. Eye problems, including corneal ulcers, can develop
rapidly and lead to loss of vision. Daily wear lenses are not
indicated for overnight wear and should not be worn while
sleeping. Clinical studies have shown the risk of serious adverse
reactions is increased when these lenses are worn overnight.
Extended wear lenses should be regularly removed for cleaning and

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disinfection or for disposal and replacement on the schedule
prescribed by your eye care practitioner. Clinical studies have
shown that there is an increased incidence of serious adverse
reactions in extended wear contact lens users as compared to daily
wear contact lens users. Studies have also shown that the risk of
serious adverse reactions increases the longer extended wear
lenses are worn before removal for cleaning and disinfection or
for disposal and replacement. Studies have also shown that
smokers have a higher incidence of adverse reactions. If you
experience eye discomfort, excessive tearing, vision changes, or
redness of the eye, immediately remove your lenses and promptly
contact your eye care practitioner. All contact lens wearers
should see their eye care practitioner as directed.
Warnings for Hydrophobic Contact Lens Products:
Warnings: PROBLEMS WITH CONTACT LENSES AND LENS CARE PRODUCTS
COULD RESULT IN SERIOUS INJURY TO THE EYE. Follow your eye care
practitioner's directions and all labeling instructions for proper
use and care of your lenses and lens care products, including the
lens case. Eye problems, including corneal ulcers, can develop
rapidly and lead to loss of vision. Daily wear lenses are not
indicated for overnight wear and should not be worn while
sleeping. If you experience eye discomfort, excessive tearing,
vision changes, redness of the eye, immediately remove your lenses
and promptly contact your eye care practitioner. All contact lens
wearers should see their eye care practitioner as directed.
Listed below is a general warning taken from the Write-It-Right example
that applies to both soft (hydrophilic) and rigid gas permeable contact
lenses:
Warning: Serious injury to the eye and loss of vision may result
from problems with contact lenses and lens care solutions. Eye
problems, including corneal ulcers and infections, can develop
rapidly. Immediately remove your lenses and call or visit your
eye care practitioner if you experience any adverse reactions such
as: eye discomfort, excessive tearing, vision changes, pain,
unusual eye discharge, sensitivity to light, or redness of the
eye.
PRECAUTIONS:
Precautions include information regarding any special care to be
exercised by the user for the safe and effective use of the device.
Listed below are (1) general precautions that pertain to all pre-
formulated solutions and tablets and (2) product specific precautions.
Include those general and specific precautions that pertain to the
device in the 510(k).
General Precautions:
• Never reuse this solution.

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• Keep the bottle tightly closed when not in use.
Special Storage Conditions.
• Use before the expiration date marked on the [carton]
[bottle] and [label] (use applicable).
• Keep out of the reach of children.
• Store at room temperature (if applicable).
Specific Precautions:
Daily Cleaners:
• Lenses should never be placed directly in the eyes from the
cleaning solution. Always rinse and disinfect lenses after
cleaning.
Periodic Cleaners:
• Tablets are not to be taken internally. If accidentally
swallowed, [describe what may occur and measures to be
taken].
• DO NOT use tablets that are broken or discolored.
• DO NOT use tablets from packages that are torn or punctured.
• Use only the special vials recommended for use with [TN].
• Use only freshly prepared enzymatic cleaning solution and
discard immediately after use.
• DO NOT soak lenses for more than XX hours because [state
reason as determined by test data (if applicable)].
• The enzymatic cleaning cycle is not a substitute for regular
cleaning or disinfecting of your contact lenses.
Chemical Disinfecting Solutions/Systems:
Hydrogen Peroxide Systems:
• DO NOT USE OVER-THE-COUNTER GENERIC HYDROGEN PEROXIDE
because [state reason].
Neutralizing Products:
• DO NOT use tablets that appear to be broken, chipped, or
discolored.
• DO NOT use tablets from packages which are torn or
punctured.

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• DO NOT substitute [TN] Neutralizer components;
• DO NOT use neutralizing tablets in a heat disinfection unit.
In-Eye Contact Lens Solutions (Lubricating/Rewetting Drops):
• Add precautions that are specific to the device in the
510(k).
ADVERSE REACTIONS (Problems and what to do):
Adverse reactions include undesirable effects, reasonably associated with the
use of the device, that may occur as part of the effect of the device or may
be unpredictable in their occurrence.
[Include the following, as applicable to the device in the 510(k).]
The following problems may occur: eyes sting, burn or
itch(irritation),comfort is less than when lens was first placed on the
eye, feeling of something in the eye (foreign body, scratched area),
excessive watering (tearing) of the eye, unusual eye secretions, redness
of the eye, reduced sharpness of vision (poor visual acuity), blurred
vision, rainbows or halos around objects, sensitivity to light
(photophobia), or dry eyes.
If you notice any of the above:
IMMEDIATELY REMOVE YOUR LENSES.
• If the discomfort or problem stops, then look closely at the lens.
• If the lens is in any way damaged, DO NOT put the lens back on
your eye. Place the lens in the storage case and contact your eye
care practitioner.
• If the lens has dirt, an eyelash, or other foreign body on it, or
the problem stops and the lens appears undamaged, thoroughly
clean, rinse and disinfect the lens, then reinsert it.
• If the problem continues, IMMEDIATELY remove the lens and consult
your eye care practitioner.
If any of the above symptoms occur, a serious condition such as
infection, corneal ulcer, neovascularization or iritis may be present.
Seek immediate professional identification of the problem and prompt
treatment to avoid serious eye damage.
All adverse reactions observed while using [TN] should be reported to:
Name of Company
Address
( 1-800-[phone number] (

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[Insert information from predicate device labeling and any other
information that is specific to the device in the 510(k).]
DIRECTIONS FOR USE:
General Instructions:
Always wash and rinse your hands before handling your lenses. This will
help to prevent eye infections by removing dirt and oils that could get
on the lenses.
Use only the solutions recommended by your eye care practitioner. Seek
advice from your eye care practitioner before making any changes to your
care regimen to ensure compatibility with lenses.
Always follow the directions for use in the labeling included with each
solution as instructions may be different for each solution.
Specific Instructions: [Include specific Directions for Use (e.g., directions
for a disinfecting regimen should describe all steps in the regimen using non-
descriptive headings such as Step 1, Step 2, Step 3...), Directions for a
disinfecting product (stand-alone) may describe the specific steps in the
regimen using descriptive headings (e.g., Cleaning, Disinfection, Rinsing...]
HOW SUPPLIED:
[Describe how device is packaged for distribution (e.g., quantity of contents,
sterile, packaged in bottle/aerosol can, and marked with lot number and
expiration date).]
MANUFACTURER OR DISTRIBUTOR NAME AND ADDRESS:
Include the information that expresses the facts: [Distributed
by/Manufactured by/Manufactured for] Address including zip code.
Printed [Month and Year]
Note: MULTI-PURPOSE SOLUTIONS
Labeling for multi-purpose solutions should combine the Description,
Actions, Indications (Uses), Precautions, Warnings, and Directions for
Use statements for each applicable indication (e.g., saline,
disinfecting solution, cleaner). Duplicate words or phrases can be
eliminated so that the resulting information is clear and
understandable. Strict attention should be paid to the labeling for
this product to assure that adequate directions for use (e.g., rubbing
and rinsing times for daily cleaning, soak times for disinfection, and
maximum storage times following disinfection) are provided for all
intended uses identified above. A contact lens solution that cannot
perform all of the functions indicated in the labeling should not be
labeled as a multi-purpose contact lens care solution.

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APPENDIX A (CONTINUED)
Bottle/Can Label:
Front:
• Product Trade Name
• Actions and Indications (e.g., cleans, disinfects, etc.)*
• Lens Statement [i.e., the type of lenses for which the device
may be used (e.g., RGP or soft (hydrophilic) lenses)]
• Net Quantity Contents**
• Sterile
Side or Back:
• [Date Opened_______/or Discard Date_______] (when
applicable)•Tamper-Resistant Statement***
• Description (i.e., Contents)
• SEE PACKAGE INSERT FOR... IMPORTANT SAFETY INFORMATION.
• Directions for Use
• Special Storage Conditions (e.g., store at room temperature)
• Keep out of Reach of Children
• Product Specific Warnings
• Insert the information that expresses the facts: [Distributed
by/Manufactured by/Manufactured for] Address including zip code
• Lot Number
• Expiration Date
___
* 21 CFR 801.61
** 21 CFR 801.62
*** 21 CFR 800.12

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APPENDIX A (CONTINUED)
Carton:
Principal Display Panel*:
• Product Trade Name
• Actions and Indications** (e.g., cleans, disinfects, etc.)
• Lens Statement (i.e., the type of lenses for which the device
may be used)
• Net Quantity Contents***
• Sterile
Outer Carton Panels:
• Description (i.e., Contents)
• Contraindications:
• If you are allergic to any ingredient in this device, DO NOT
use.
• Any additional known contraindications for specific device.
• Directions for Use (or reference Package Insert)
• Special Storage Conditions (e.g., store at room temperature)
• SEE PACKAGE INSERT FOR... IMPORTANT SAFETY INFORMATION.
• Keep out of Reach of Children
• Tamper-Resistant Statement****
• Product Specific Warnings
• Insert the information that expresses the facts: [Distributed
by/Manufactured by/Manufactured for] Address including zip code
• Lot Number
• Expiration Date
___
* 21 CFR 801.60
** 21 CFR 801.61
*** 21 CFR 801.62
**** 21 CFR 800.12

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APPENDIX A (CONTINUED)
Package Insert Using Write-it-Right Principles
Included below is an example of a package insert for aerosol saline solution.
This example incorporates principles taken from labeling entitled, "Improved
Patient Instructions for Care of Soft Contact Lenses," that was prepared by a
CDRH focus group based upon a study using consumers and Write-It-Right
principles. This example differs somewhat in format from predicate device
package inserts in that some sections have been rearranged, while others have
been combined in an effort to eliminate duplication. In writing this package
insert, icons were used to focus on various information. Warnings and
precautions were boxed and strategically placed throughout the package insert
to highlight the consumer's awareness to special considerations. Applicants
developing new labeling or needing to bring their labeling up to date may
choose to follow this sample package insert format or follow the format in
predicate device labeling.
SAMPLE PACKAGE INSERT FOR MULTI-DOSE UNPRESERVED SALINE
(packaged in aerosol container)
IMPORTANT: Please read carefully and keep this information for future use.
[Trade Name (TN)]
WARNING
Serious injury to the eye and loss of vision may result
from problems with contact lenses and lens care
solutions. Eye problems, including corneal ulcers and
infections, can develop rapidly. Immediately remove
your lenses and call or visit your eye care practitioner
if you experience any adverse reactions such as: eye
discomfort, excessive tearing, vision changes, pain,
unusual eye discharge, sensitivity to light, or redness
of the eye.
[Note: Use only those indications included in the labeling that have been
approved in a PMA or cleared in a 510(k).]
INDICATIONS/ACTIONS:
[TN] saline is indicated for use with (specify type) contact lenses for
rinsing after cleaning to remove loosened debris and cleaning solution,
rinsing prior to lens insertion, keeping lenses wet during heat disinfection,
storage after disinfection, as a diluent for dissolving lens care tablets
(e.g., enzyme or disinfecting tablets), and as a diluent for use in hydrogen
peroxide disinfection systems (limited use).

` 68
DIRECTIONS FOR USE:
General Instructions:
Always wash and rinse your hands before handling your lenses. This will
help to prevent eye infections by removing dirt and oils that could get
on the lenses.
Use only the solutions recommended by your eye care practitioner. Seek
advice from your eye care practitioner before making any changes to your
care regimen to ensure compatibility with lenses.
Always follow the directions for use in the labeling included with each
solution as instructions may be different for each solution.
WARNING
To avoid contaminating your solution or your lenses:
• DO NOT transfer this solution into other bottles or
containers.
• DO NOT touch nozzle tip of the can to any surface.
STEP 1. RINSE
WARNING
• Contents under pressure, DO NOT spray directly into the
eye, as serious injury to the eye may result.
• Always spray a small amount into the sink to clear the
nozzle of contaminants before spraying the saline onto
your lenses.
F Rinse the lens thoroughly with fresh saline solution. Direct a
stream of saline on both sides of the lens for at least 10
seconds.
STEP 2. HEAT DISINFECTION
F Place each lens in the appropriate chamber of the storage case.
F Fill each chamber with enough [TN] to completely cover the lenses.
F Close the lens case tightly so that the lens will not dry out.
F Place the lens storage case in your heat disinfection unit.

` 69
F Follow the instructions that come with your heat disinfection
unit.
F Keep the lenses in the unopened lens case until you are ready to
wear them.
CAUTION
• Never reuse the solution
• Store at room temperature
• Keep out of reach of children
• Use before expiration date marked on the container
WARNING
• To minimize the risk of contamination, DO NOT store
lenses in saline that has not been heat disinfected.
WARNING
CONTENTS UNDER PRESSURE
• DO NOT puncture or incinerate can.
• DO NOT store at temperatures above 120oF.
NOTE: This product may be used to dissolve enzyme tablets or as a
neutralizing solution in some hydrogen peroxide systems. Follow the
Directions for Use in the labeling accompanying your enzyme tablets or
hydrogen peroxide system.
All contact lens wearers should see their eye care practitioner as often
as directed. If your lenses are for extended wear, your eye care
practitioner may prescribe more frequent visits to carefully monitor
your ocular health.
DESCRIPTION/CONTENTS:
[TN] is a sterile isotonic [the following as applicable: buffered/
unpreserved] solution containing [list all ingredients including any
propellant(s)].
CONTRAINDICATIONS:
There are no known contraindications for use of this product OR
If you are allergic to any ingredient in [TN], DO NOT use.

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ADVERSE REACTIONS:
All adverse reactions observed while using [TN] should be reported to:
Name of Company
Address
( 1-800-[phone number] (
HOW SUPPLIED:
[TN] is supplied sterile in [] fl. oz. aerosol cans. Each can is marked with
the lot number and expiration date.
Insert the information that expresses the facts: [Distributed by/Manufactured
by/Manufactured for] Address including zip code
Printed [Month and Year]

` 71
LABELING--APPENDIX B
Lens Cases
[Include applicable information under the following headings. Applicants
should use predicate device labeling as guidance].
TRADE NAME:
INDICATIONS: For storage of [soft (hydrophilic)/rigid gas permeable/and hard]
contact lenses during [heat disinfection/heat or chemical disinfection (use
applicable)].
Include additional limiting information (if applicable):
• For storage only - not for use as a container for heat or
chemical disinfection.
• Use for storage during chemical disinfection only. DO NOT
USE WITH HEAT.
DIRECTIONS FOR USE:
General Instructions: [Include preparing the lens case for use and how
to care for the lens case daily.]
Specific Instructions: [Include step-by-step instructions for use.]
WARNINGS:
Warning for All Lens Cases:
• Lens cases can be a significant source of microbial contamination.
To help prevent eye infections, lens cases should be cleaned,
rinsed and air dried every day; and replaced frequently (as
recommended by the manufacturer).
Warning for Lens Cases Indicated for Use in Chemical Disinfection Only:
• Use of this lens case with heat may cause warpage. USE FOR
STORAGE DURING CHEMICAL DISINFECTION ONLY. DO NOT USE WITH HEAT.
ENDING:
• Include the information that expresses the facts: [Distributed
by/Manufactured by/Manufactured for] Address including zip code
• Lot No.
• Printed [Month and Year]

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LABELING--APPENDIX C
Heat Disinfection Units
Applicants should follow the format of predicate device labeling for heat
disinfection units.
The heat disinfection unit labeling should comply with 21 CFR 801.15, "Medical
devices; prominence of required label statements," and 21 CFR 801.60,
"Principal display panel."
Heat disinfection labeling should contain explanatory labeling of the heat
indicator function. Listed below are models of what should be minimal
acceptable labeling pertaining to indicator and heater function for contact
lens heat disinfection units that utilize either a thermostat or electronic
timer to automatically control the disinfection cycle. The applicant should
pick the appropriate indicator information and integrate it into the labeling.
Alternate wording may be used, but the meaning of all labeling statements
should be unchanged. Emphasis shown in the model labeling by use of uppercase
lettering is considered to be essential. Both carton and user instruction
paragraphs should be located and emphasized by use of bold faced type or
contrasting color so as to elicit the attention of the user.
1. MODEL LABELING FOR UNITS WITH LIGHT FOR POSITIVE FUNCTION/FAILURE
INDICATOR
Package Labeling:
Principal Display Panel:
HEATER INDICATOR LIGHT - This unit uses a light to indicate the
start and finish of the disinfection cycle.
READ USER INSTRUCTIONS CAREFULLY
Any Panel:
THE UNIT HAS A LIGHT TO INDICATE THE START AND FINISH OF THE
DISINFECTION CYCLE THAT ONLY LIGHTS WHEN THE HEATER IS ON. ALLOW
___ MINUTES COOLING TIME AFTER THE LIGHT GOES OFF BEFORE REMOVING
LENSES.
User Instructions:
CAUTION: Observe the light indicator to confirm that the unit is
operating correctly. It must turn on when the unit is started and
turn off after ___ to ___ minutes. REPLACE THE UNIT if the light
does not turn on when the unit is started or does not turn off
within ____ minutes after being started.

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2. MODEL LABELING FOR UNITS WITH A TEMPERATURE SENSOR (NON-LIGHT) INDICATOR
FOR POSITIVE FUNCTION/FAILURE INDICATOR
Package Labeling:
Principal Display Panel:
HEAT SENSOR - This unit uses a heat sensor to indicate the start
and finish of the disinfection cycle by (describe how).
READ USER INSTRUCTIONS CAREFULLY
Any Panel:
THE UNIT HAS A HEAT SENSITIVE INDICATOR THAT TELLS WHEN
DISINFECTION STARTS BY CHANGING FROM ______ TO ______ AND TELLS
WHEN THE UNIT IS COOL ENOUGH TO REMOVE LENSES SAFELY BY CHANGING
FROM _____ TO _____.
User Instructions:
CAUTION: Observe the heat sensor to confirm that the unit is
operating correctly. It must change from ____ to ____ after
starting the disinfection cycle. Observe the heat sensor again
after completion of the disinfection cycle and prior to unplugging
the unit. It must change back from ____ to ____. REPLACE THE
UNIT if the heat sensor does not change.
Carton Label:
TRADE NAME:
INDICATIONS:
DIRECTIONS FOR USE:
Before First Use: [Provide necessary instructions.]
Heat (Thermal) Disinfection: [Provide step-by-step instructions
for disinfecting lenses.]
Maintenance of Your Heat Disinfection Unit [Provide necessary
maintenance instructions.]
CONTRAINDICATIONS: [DO NOT use with rigid gas permeable or hard contact
lenses.]

` 74
WARNINGS:
General Warnings:
• DO NOT IMMERSE OR RINSE UNIT IN TAP WATER. IF SALINE, WATER, OR
OTHER LIQUIDS COME IN CONTACT WITH THE EXTERIOR OF THE UNIT,
_______________, AND ______________, IMMEDIATELY WIPE DRY BEFORE
USING.
• [Include other general warnings as applicable.]
Warnings for Electrical Device (as applicable):
SAVE THESE INSTRUCTIONS:
To reduce the risk of electrocution:
• DO NOT operate your [TN] if the unit is wet. Dry exterior
surfaces before using.
• DO NOT touch the [TN] or the removable electrical plug with
wet hands.
• Always unplug this product immediately after using.
• DO NOT use while bathing.
• DO NOT place or store product where it can fall or be pulled
into a bath or sink.
• DO NOT place in or drop into water or other liquid.
To reduce the risk of burns, electrocution, fire or injury:
• Close supervision is necessary when this product is used by,
on, or near children or invalids. This is not a toy for
children.
• Never operate this product if it has a damaged cord or plug,
if it is not working properly, if it has been dropped or
damaged, or dropped into water.
• DO NOT use outdoors or operate where aerosol products are
being used or where oxygen is being administered.
• Electrical shock can occur if the unit is wet or if the
electrical plug is not completely engaged in the receptacle.
DESCRIPTION: [Include description of device, including indicator
and how it works.]

` 75
ENDING: Include the information that expresses the facts:
• [Distributed by/Manufactured by/Manufactured for] Address
including zip code
• Lot or Serial No.
• Printed [Month and Year]

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LABELING--APPENDIX D
Salt Tablets/Capsules Systems:
On September 21, 1987, CDRH sent a letter to salt tablet PMA owners and
interested persons advising them that specific directions for use and warnings
should be used in salt tablet labeling to ensure safe and effective use of
homemade saline from salt tablets. PMA owners subsequently revised their
labeling in accordance with CDRH's letter. No changes have been made in
CDRH's policy since the September 21 letter issued. The letter advised PMA
owners that CDRH believes that there is sufficient scientific evidence to
demonstrate that (1) salt tablets/capsules saline should NOT be used in
conjunction with chemical disinfection systems for contact lens care and (2)
the continued use of salt tablets/capsules saline in conjunction with heat
disinfection requires greater consumer awareness that salt tablets/capsules
saline should NEVER be used FOLLOWING heat disinfection. The letter further
stated that the following labeling (Warnings and Indications for Use) should
be used for salt tablets/capsules system labeling to provide continuing safety
and effectiveness of the device for its intended use. All labeling for salt
tablets/capsules systems should follow the format of predicate device labeling
that has been revised after the September 21, 1987 letter issued and include
the information listed below:
1. Carton Labeling
The front panel of the salt tablets/capsules carton should prominently
display the following warning:
WARNING: USE THIS PRODUCT EXACTLY AS DIRECTED. The package insert for
this product contains WARNINGS and SAFETY INFORMATION. PLEASE READ IT
CAREFULLY.
2. INDICATIONS: The Indications for Use statement should read as follows:
For rinsing and for use during heat disinfection and storage
of soft (hydrophilic) contact lenses.
Rinsing PRIOR to heat disinfection only.
Storage DURING heat disinfection only.
3. Package Insert
General Warning Statements - The package insert for this product should
prominently display the following warnings:
SALT TABLETS/CAPSULES
WARNINGS: AN ASSOCIATION HAS BEEN ESTABLISHED BETWEEN IMPROPER USE OF
SALT TABLETS/CAPSULES SALINE AND SERIOUS EYE INFECTIONS THAT
MAY RESULT IN LOSS OF SIGHT.
DISTILLED WATER IS A NON-STERILE PRODUCT. THE USE OF NON-
STERILE PRODUCTS IN THE PREPARATION OF CONTACT LENS

` 77
SOLUTIONS MAY LEAD TO CONTAMINATION OF LENSES BY
MICROORGANISMS INCLUDING ACANTHAMOEBA WHICH CAN CAUSE
SERIOUS EYE INFECTIONS AND RESULT IN PERMANENT VISUAL LOSS.
WHILE CHEMICAL DISINFECTION SOLUTIONS, INCLUDING HYDROGEN
PEROXIDE, ARE EFFECTIVE IN KILLING MICROORGANISMS THAT
COMMONLY PRODUCE EYE INFECTIONS, THEY MAY NOT BE EFFECTIVE
AGAINST THE ACANTHAMOEBA ORGANISM. FOLLOW THESE REVISED
INSTRUCTIONS CAREFULLY, OR DISCONTINUE USE OF SALT
TABLETS/CAPSULES SALINE.
• NEVER USE SALT TABLETS/CAPSULES SALINE SOLUTION WITH
CHEMICAL OR HYDROGEN PEROXIDE DISINFECTION OF CONTACT
LENSES.
• NEVER USE SALT TABLETS/CAPSULES SALINE SOLUTION AS A
RINSE AFTER ANY DISINFECTION (use only a commercially
prepared sterile saline solution for rinsing after
disinfection).
• NEVER USE SALT TABLETS/CAPSULES SALINE SOLUTION
DIRECTLY IN THE EYE.
DIRECTIONS FOR USE:
DESCRIPTION/CONTENTS:
PRECAUTIONS:
CONTRAINDICATIONS:
ADVERSE REACTIONS:
HOW SUPPLIED:
ENDING:
• Insert the information that expresses the facts: [Distributed
by/Manufactured by/Manufactured for] Address including zip code
• Lot Number
• Expiration Date
• Printed [Month and Year]

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LABELING--APPENDIX E
Contact Lens Accessories (Mechanical Cleaning Aids)
[Include applicable information under the following headings. Applicants
should use predicate device labeling as guidance].
TRADE NAME:
INDICATIONS/ACTIONS: [Include specific indications (e.g., [TN] is indicated
for use with contact lens cleaning solutions to aid in cleaning by minimizing
hand contact with lenses.)]
CONTRAINDICATIONS: [If there are no known contraindications, add the
statement: "There are no known contraindications associated with the use of
this device." If there are contraindications, list them.]
DIRECTIONS FOR USE: [Include step-by-step directions for use including what
products can be used with the device.]
WARNINGS: [Include warnings applicable to the device in the 510(k).]
Warnings for Electrical Device: [Include the information from the
labeling example for Heat Disinfection Units (Labeling--Appendix C), if
applicable].
PRECAUTIONS:
• To avoid damage to lenses, follow precautions in the contact lens
solution labeling.
• [Additional precautions specific to the device in the 510(k).]
ADVERSE REACTIONS:
ENDING:
• Include the information that expresses the facts: [Distributed
by/Manufactured by/Manufactured for] Address including zip code
• Lot or Serial No.
• Printed [Month and Year]

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LABELING--APPENDIX F
Contact Lens Accessories (Accessory Cleaning Pads)
[Include applicable information under the following headings. Applicants
should use predicate device labeling as guidance].
TRADE NAME:
INDICATIONS/ACTIONS: [Include specific indications (e.g., [TN] is indicated
for use with contact lens cleaning solutions to aid in cleaning by minimizing
hand contact with lenses).]
CONTRAINDICATIONS: [If there are no known contraindications, add the
statement: "There are no known contraindications associated with the use of
this device." If there are contraindications, list them.]
DIRECTIONS FOR USE: [Include step-by-step directions for use, including how
to clean the pad, and how often to replace it.]
WARNINGS:
• [Add for pads that are to be reused.] To help avoid contamination
and eye infection, clean and air-dry pad every day; replace pad
every (insert number) day(s).
• [Add for pads that are disposable (i.e., use once and throw
away).] To help avoid contamination and eye infection, discard
pad after each use.
• [Additional warnings applicable to the device in the 510(k).]
PRECAUTIONS:
• To avoid damage to lenses, use exactly as instructed in the
contact lens solution labeling.
• [Additional precautions specific to the device in the 510(k).]
ADVERSE REACTIONS:
ENDING:
• Include the information that expresses the facts: [Distributed
by/Manufactured by/Manufactured for] Address including zip code
• Lot No.
• Printed [Month and Year]

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VI. RECOMMENDED TEST METHODS
Page
INTRODUCTION................................................................81
CHEMISTRY (CHEM)
Preservative Uptake/Release Test Procedures (Appendix A)..............82
Cleaning Effectiveness (Appendix B)...................................86
Solution Compatibility (Appendix C)...................................88
MICROBIOLOGY (MICRO)
Preservative Effectiveness (Appendix A)...............................89
Disinfecting Products (Appendix B)....................................94
Bacteriostasis Test (Appendix C).....................................105
Membrane Filtration Procedure (Appendix D)...........................110
TOXICOLOGY (TOX)
Introduction, Minimum Recommended Testing, Additional
Recommended Testing, Toxicology Testing for Container/
Closure Systems (Appendix A).........................................113
Acute Oral Toxicity (Appendix B).....................................116
CLINICAL (CLIN)
Introduction and Clinical Study Summary (Appendix A).................119
Clinical Protocol Suggestions (Appendix B)...........................126
Slit Lamp Findings Classification Scale (Appendix C).................135
Informative Summary Reporting Tables (Appendix D)....................139
Trend Analysis Profile (Appendix E)..................................157
SHELF-LIFE PROTOCOL........................................................160

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INTRODUCTION
This section of the guidance includes recommended preclinical and clinical
test methods designed to provide data to assess substantial equivalence of
contact lens care products to legally marketed devices. Whenever possible,
the guidance references applicable standards that have been finalized and have
been found acceptable for use by CDRH.
CDRH is actively working on the development of contact lens product standards
with the American National Standards Institute (ANSI) and the International
Organization of Standards (ISO) in an effort to harmonize our requirements and
recommended test methods with voluntary standards being developed nationally
and internationally. Although some contact lens care product standards have
been completed and published for use, a number of important standards are
currently under development and have not been completed or adopted at this
time. For those standards currently under development, CDRH has attempted to
harmonize our requirements and recommended test methods, to the extent
possible, with standards being drafted at this time. For purposes of
harmonization, elements of those draft standards that CDRH finds acceptable
have been incorporated into the appropriate sections of this guidance or into
the recommended test methods included in this section.

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CHEM--APPENDIX A
PRESERVATIVE UPTAKE/RELEASE TEST PROCEDURES
The purpose of this test is to determine preservative uptake/release in
solutions containing new preservatives for contact lens use. The results of
these test data will be used to predict the potential for a preservative
related toxicity, as well as the potential for inducing a sensitivity/allergic
response associated with the contact lens care products.
The test procedures outlined here have been accepted by CDRH for the
quantitative analysis of the uptake/release of preservatives, such as
thimerosal, chlorhexidine, and benzalkonium chloride, in contact lenses. It
is the responsibility of the applicant to select a validated chemical method
for the quantitative analysis of the uptake/release of the preservative from
the lens, whether it be thimerosal, chlorhexidine, benzalkonium chloride or
other newer agents.
In general, a thermodynamically defined "plateau" of total* accumulation of
preservative on the lens should be demonstrated for the recommended lens care
regimen. Alternatively, the preservative uptake/release studies through
equilibration studies can substitute cycling studies (e.g., each lens is
soaked in 100 ml care solution at room temperature for 4 days, 8 days, and 12
days or longer).
At least three data points, each separated by at least 20 cycles under the
recommended lens care regimen, should be submitted. Each data point should be
expressed in terms of the average value, standard deviation, and number of
measurements. A statistical analysis should be performed to ensure that it
reaches a plateau area. For hydrophilic contact lenses, it should be
expressed as μg preservative/mg dry lens; however, for hydrophobic contact
lenses, it should be expressed as μg preservative/surface area of lens in cm2.
A. Thimerosal Uptake/Release Studies of Hydrophilic and Hydrophobic Lens
Materials by Atomic Absorption Spectrometry:
1. Sample Preparations
Each lens, after cycling under the recommended care regimen or
after a reasonable soaking time in the thimerosal preserved care
solution, is placed in a borosilicate vial and bathed in 1 ml
isotonic pH = 7.0 buffered saline solution at 35oC for 15 hours
(preservative release study). The lens is removed from the vial,
blot-dried, and placed in another borosilicate vial which is used
for the preservative uptake study.
2. Preservative Uptake Study
Five ml of concentrated sulfuric:nitric acid (3:1 by volume**) are
added to the vial containing the lens. The vial is heated, gently
______
*Total accumulation of preservative on the lens is a sum of preservative
uptake and preservative release data.
______
**2:l by volume for hydrophilic plastic lenses.

` 83
at first on a hot plate until the lens is decomposed. Care should
be taken during heating to avoid charring. The vial is then
heated strongly to remove all traces of nitric acid, which is
determined visually by the presence of white vapor instead of
brown vapor (nitrous oxide) inside the vial. If charring occurs,
a few drops of concentrated nitric acid are added and the sample
reheated.
The entire sample is employed for the mercury determination using
cold vapor atomic absorption spectrometry. Two control lenses,
which have been soaked in an isotonic pH = 7.0 buffered saline
solution for the duration of the study (35oC for 15 hours), are
decomposed and treated as the test lens. Absorbance values for
the sample lenses are corrected by subtracting the absorbance
value of the control lens.
3. Preservative Release Study
Five ml of concentrated sulfuric:nitric acid (3:1 by volume**) are
added to the vial containing lens leachate. The solution is
treated as the test lens. A control solution (an isotonic pH =
7.0 buffered saline solution) is also treated as the test lens.
Absorbance values for the lens leachates are corrected by
subtracting the absorbance value of the control solution.
4. Standard Curve
Five ml of concentrated sulfuric:nitric acid (3:1 by volume**) are
added to the vial containing a known concentration of thimerosal
standard. The standard solution is treated as the test lens. A
reagent blank (concentrated sulfuric:nitric acid = 3.1 by volume)
is also treated as the test lens. Absorbance values for the
standard solutions are corrected by subtracting the absorbance
value of the reagent blank.
B. Chlorhexidine Uptake/Release Studies of Hydrophilic and Hydrophobic Lens
Materials by 14C-Labeled Technique:
The procedure for chlorhexidine (CHG) can be used for any preservative
which can be tagged with a non-labile radioactive label.
CHG accumulation by contact lenses is assessed by 14C counting of
radiolabeled CHG associated with the lens after the recommended care
regimen. The modified procedure of MacKeen and Green*** specifically
designed for preservative determination in contact lenses is briefly
described as follows:
____
***MacKeen, D.L. and Green, K.: Chlorhexidine Kinetics of
Hydrophilic Contact Lenses; J. Pharm. Pharmacol., 30: 578-682, 1978.
MacKeen, D.L. and Green, K.: Chlorhexidine Kinetics in Hard Contact Lenses;
J. Pharm. Pharmacol., 31: 714-716, 1979.

` 84
1. Sample Preparations
Radiolabeled 14C-CHG is added to the care solution containing CHG.
Each lens after cycling under the recommended care regimen
containing 14C-CHG or after a reasonable soaking time in 14C-CHG
preserved care solution is placed in a scintillation vial and
bathed in 1 ml isotonic pH = 7.0 buffered saline solution at 35oC
for 15 hours (preservative release study). The lens is removed
from the vial, blot-dried, and placed in another scintillation
vial which is used for the preservative uptake study.
2. Preservative Uptake Study
Three ml of concentrated sulfuric:nitric acid (3:1 by volume**)
are added to the vial containing the lens. The vial is heated to
boiling. After cooling to room temperature, duplicate 100 μl
samples are taken of the resultant solution, mixed with 1 ml of
deionized water and 10 ml of Aquasol (New England Nuclear
Corporation) with vigorous agitation. After cooling, the samples
are counted. The control lens, just removed from the shipping
container, is solubilized and treated as the test lens. The
counts for the test lenses are corrected by subtracting the counts
of the control lens.
3. Preservative Release Study
Three ml of concentrated sulfuric:nitric acid (3:1 by volume**)
are added to the vial containing lens leachate. The vial is
heated to boiling. After cooling to room temperature, duplicate
100 μl are mixed with 1 ml of deionized water and 10 ml of Aquasol
and counted. Duplicate 100 μl of a control solution (an isotonic
pH = 7.0 buffered saline solution) are also treated in the same
way. The counts for lens leachate are corrected by subtracting
the counts of the control solution.
4. Standard
Three ml of concentrated sulfuric:nitric acid (3:1 by volume**)
are added to the scintillation vial containing 100 μl of 14C-CHG
standard solution. The vial is heated to boiling. After cooling
to room temperature, duplicate 100 μl samples are taken of the
resultant solution, mixed with 1 ml deionized water and 10 ml of
Aquasol with vigorous agitation. After cooling, the samples are
counted.
C. Chlorhexidine Uptake/Release Studies of Hydrophilic Lens Materials by
High Pressure Liquid Chromatography (HPLC)
This procedure for chlorhexidine uptake/release studies can be used for
hydrophilic lens materials which show a strong absorption and adsorption
to CHG through electrostatic interactions.

` 85
The modified procedure of Stevens et al+ specifically designed for
preservative determination in hydrophilic lens materials is briefly
described as follows.
Lenses are soaked in a minimum volume of care solution at room
temperature for 4 days, 8 days, and 12 days or longer. The CHG
accumulation by hydrophilic lens materials is assessed by a difference
in concentrations of CHG in the care solution before and after lens
soaking. After soaking, the lens is removed and placed in 1 ml
isotonic pH = 7.0 buffered solution at 35oC for 15 hours (preservative
release study). The CHG concentrations in both soaking and elution
solutions are determined by injecting sample aliquots of 20 μl directly
onto the HPLC column and calculating from the standard. The detection
limit, reproducibility, and reliability should be assessed compared to
preservative uptake/release studies to ensure the suitability of this
method.
D. Benzalkonium Chloride (BAK) Uptake/Release Studies of Hydrophobic Lens
Materials by Laser Fluorescence Spectroscopy++
1. Sample Preparation
After cycling under the recommended care regimen or after a
reasonable soaking time in BAK preserved care solution, each lens
is placed in a vial and bathed in 1 ml isotonic pH = 7.0 buffered
saline solution at 35oC for 15 hours (preservative release study).
The lens that is removed from the vial and air-dried is used for
the preservative uptake study.
2. Preservative Uptake Study
Adsorbed BAK is measured by laser fluorescence spectroscopy with
an argon laser. The excitation intensity is on the order of 4 x
10-6 Einsteins/second, providing a fluorescence spectrum level of
103 counts/second at the phototube. For detection, a Hammamatsu
photomultiplier tube biased with a Keithley microammeter/high
voltage power is used. Monochromators are double JY 0.5 meter
holographic gratings.
3. Preservative Release Study
Total adsorbed BAK on the lens is also measured by laser
fluorescence spectroscopy. The difference between total adsorbed
BAK and adsorbed BAK is the value for preservative release study.
_____
+Stevens, L.E., Durrwachter, J.R., and Helton, D.O.: Analysis of
Chlorhexidine Sorption in Soft Contact Lenses by Catalytic Oxidation of
14C-Chlorhexidine and by Liquid Chromatography: J. Pharm. Sci., 75: 83-86,
1986.
_____
++Wong, M.P., Dziabo, A.J., and Kiral, R.M.: Dynamics of BAK
Adsorption by Silicone Acrylate Lenses; Contact Lens Spectrum, November.
49-53, 1986.

` 86
CHEM--APPENDIX B
CLEANING EFFECTIVENESS
Determination of the Critical Micelle Concentration of a Surfactant (or
Surfactant System) in a Lens Care Product Having a Cleaning Claim
In an aqueous solution of a surfactant, the surfactant is molecularly
dispersed at low concentrations. At higher concentrations, however, when a
certain critical concentration is reached, the molecules form micelles. These
micelles are in equilibrium with the free surfactant molecules. The
concentration that must be reached in order that micelles are formed is called
the critical micelle concentration. Adequate cleaning effectiveness of a
daily cleaner can be demonstrated in vitro by determining that the
concentration of a surfactant (or surfactants) in a daily cleaner are higher
than the critical micelle concentration of surfactant (or surfactants).
Many physical properties of the surfactant solution when plotted against the
concentration show more or less sudden changes at the critical micelle
concentration. By measuring such properties as electrical conductivity,
interfacial tension, surface tension, refractive index, viscosity, and light
scattering as a function of the concentration of the surfactant, the critical
micelle concentration is determined as the concentration at which the property
versus concentration curve shows a change in slope. The hydrophobic part of
the surfactant molecule is situated at the inside of the micelle, the
hydrophilic part at the outside. Inside the micelles lipophilic substances
may be solubilized.
The purpose of a daily cleaner is to remove loosely held lens deposits on the
lens surface. Generally, a daily cleaner contains at least a surfactant which
lowers surface tension of the solution to facilitate removal of loosely held
lens deposits on the lens surface in conjunction with mechanical means (e.g.,
fingers). The concentration of a surfactant (or surfactants) in a daily
cleaner should be sufficient enough to be higher than the critical micelle
concentration of surfactant (or surfactants). The critical micelle
concentration of surfactant may be significantly affected by pH, tonicity, and
other inactive ingredients in the daily cleaner.
The purpose of this appendix is not intended to list all methods to determine
the critical micelle concentration of surfactant (or surfactants). Rather, we
are providing a simple method such as measuring surface tension of a
surfactant (or surfactants) in a device medium to determine the critical
micelle concentration.
1. Solution 1: Prepare the daily cleaner medium (i.e., the daily cleaner
without surfactants).
2. Solution 2: Prepare a reasonable concentration of the surfactant system
(if more than one surfactant is in the daily cleaner, the weight or mole
ratio of the surfactant system should be the same as the one in the
daily cleaner).
3. Solution 3: Prepare varying concentrations of the surfactant system in
the daily cleaner medium by diluting Solution 2 with Solution 1.

` 87
4. Measure surface tension of Solution 3 by the Tensiometer.
5. Plot surface tension versus log concentration of surfactant system in
the daily cleaner medium (Solution 3) and perform least square linear
regressions to determine the critical micelle concentration.

` 88
CHEM--APPENDIX C
SOLUTION COMPATIBILITY TEST PROTOCOL
The purpose of this test is to assess the effect of a contact lens solution on
contact lens parameters and solution compatibility under the recommended care
regimen. CDRH does not believe that data will ordinarily be required to be
submitted in the 510(k) if the solution is essentially identical to the
predicate device in terms of active and inactive ingredients. For purpose of
this guidance, our focus is on active ingredients. However, manufacturers
should also assess the effects of inactive ingredients on such factors as pH
and tonicity, which could significantly affect solution compatibility. For
hydrophilic contact lenses, CDRH considers tinted contact lenses to represent
the worst case. The following is a suggested protocol:
1. Number of Cycles:
30 cycles for heat disinfection regimen
30 cycles for chemical or hydrogen peroxide disinfection regimen
2. Number of Lenses:
For hydrophilic contact lenses
Group I: at least 10 lenses with low powers
Group IV: at least 10 lenses with low powers
For hydrophobic contact lenses
Number of lenses should be equally divided between the lens groups for
which the solution is indicated, for a total of 20 lenses
3. Parameters Monitored:
Optical parameters: power, base curve, and diameter
Physical appearance: discoloration and clarity
Chemical parameters: tint (if applicable)
ultraviolet absorption (if applicable)
4. Test Method:
a. Record optical, physical, and chemical parameters before cycling.
b. Flex lenses in a manner to simulate removal of the lens from the
eye (not applicable for hydrophobic lenses).
c. Clean, rinse, and disinfect lenses (including handling procedures)
as required in the labeling for the recommended care regimen.
d. Repeat (b) if applicable and (c) for each cycle up to 30 cycles
with the appropriate heat disinfection, chemical disinfection, and
hydrogen peroxide regimen.
e. Record optical, physical, and chemical parameters after cycling.
f. Summarize and discuss the test results.

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MICRO--APPENDIX A
PRESERVATIVE EFFICACY OF MULTI-DOSE
PRESERVED CONTACT LENS CARE PRODUCTS
I. PRINCIPLE
The antimicrobial activity test uses a standard inoculum of a
representative range of microorganisms to challenge a preserved product
and establishes the extent of viability loss at predetermined time
intervals. The size of the microbial challenge chosen in this test is
not intended to be representative of the likely challenge in practice
but to provide countable numbers from which estimation of the rate and
extent of viability loss can be determined. The capability of the
product to prevent microbial growth is evaluated.
In carrying out the test for antimicrobial activity the qualitative and
quantitative composition of the product at the time of testing should be
known by either analytical testing or extrapolation.
Appropriate measures should be taken to inactivate or remove residual
antimicrobial agents during recovery of survivors, and the effectiveness
of these measures should be demonstrated.
Three lots of product should be tested. Each lot of product should be
tested with a separate inoculum preparation for each challenge organism.
II. MATERIALS & REAGENTS
A. Test Organisms
Pseudomonas aeruginosa NCIMB 8626 ATCC 9027
Staphylococcus aureus NCTC 10788 ATCC 6538
Escherichia coli NCIB 8245 ATCC 8739
Candida albicans NCPF 3179 ATCC 10231
Aspergillus niger IMI 149007 ATCC 16404
B. Test Media
Tryptone Soya Broth (TSB), Tryptone Soya Agar (TSA), Sabouraud
Dextrose Agar (SDA), Dulbecco's Phosphate Buffered Saline without
calcium chloride and magnesium chloride (DPBS): 200 mg/l KCl, 200
mg/l KH2PO4, 8000 mg/l NaCl, and 2,160 mg/l Na2HPO4•7H2O or suitable
diluent; Dulbecco's Phosphate Buffered Saline plus 0.05% w/v
polysorbate 80 (DPBST) or suitable diluent
Validated neutralizing agents/media as required (e.g., Dey-Engley
Neutralizing Broth and Agar).

` 90
C. Test Equipment
Sterile pipettes, glass beads, swabs, tubes, 100 X 20 mm petri
dishes, etc., as required. Suitable instruments for
spectrophotometric determination of cell density, for colony
counting, and for centrifugation.
D. Test Samples
Product samples to be tested should be representative of the
product to be marketed. Aliquots should be taken directly from
the final product container immediately prior to testing.
III. TEST METHOD
A. Culture Maintenance
Cultures should be maintained in the manner recommended by the
curator of the appropriate culture collection. Cultures should be
no greater than 5 passes removed from the depository stock (ATCC,
NCIB, NCTC, NCPF or other recognized culture depository).
B. Preparation of Microbial Challenge (Inoculum)
Test organisms should be cultured on agar as in Table 1.
Table 1: Media & Incubation Conditions for Growth of
Challenge Organisms
Organism Medium Incubation
Temp oC Time
Pseudomonas aeruginosa TSA 30-35 18-24h
Staphylococcus aureus TSA 30-35 18-24h
Escherichia coli TSA 30-35 18-24h
Candida albicans SDA
SDA 20-25 42-48 or
30-35 18-24h
Aspergillus niger SDA 20-25 7 days
To harvest all cultures, use sterile DPBST or a suitable diluent,
washing the surface growth and transfer to a suitable vessel. The
spore suspensions may be filtered through sterile glass wool,
cotton gauze, or cheese cloth to remove hyphal fragments.
After harvesting, the cultured organisms may be washed using
centrifugation. If centrifugation is used, each centrifugation
should be conducted at 2-25oC for no longer than 10 minutes at
4000 x g or less. The bacterial suspensions may be filtered
(e.g., 3 - 5 μm pore size) to produce a single cell dispersion.
All challenge cell suspensions should then be adjusted with DPBST
or other suitable diluent to 1 X 107 - 1 X 108 colony forming
units (cfu)/ml. The approximate cell concentration may be
estimated by measuring the turbidity of the suspension or a

` 91
dilution of the suspension using a spectrophotometer. The actual
concentration of cfu/ml should be determined for each suspension
by the plate count method at the time of the test.
Bacterial and yeast cell suspensions should be used on the day of
preparation. Bacterial and yeast cells may lose viability and
resistance if not used on the day of preparation. Spore
suspensions may be used up to 7 days following preparation by
storage under refrigeration (Avg. 4+2°C).
C. Test Procedure
1. Prepare one tube containing a minimum of 10 ml of test
solution per challenge organism. Inoculate the sample tube
of the product to be tested with a suspension of test
organisms sufficient to provide a final count of 1.0 X 105 -
1.0 X 106 cfu/ml. The volume of inoculum should not exceed
1% of the sample volume. Ensure dispersion of the inoculum
by adequate mixing.
2. Store inoculated product at 20-25°C. Temperature should be
monitored using a calibrated device and documented. If
sensitive to light the product should be protected during
the period of the test.
3. Take 1.0 ml aliquots of the inoculated product for
determination of viable count at 7 days and 14 days.
4. Each sample is rechallenged as in III.C.1 on day 14 after
taking the 14-day sample. Use an inoculum level of 1.0 X
104 - 1.0 X 105 cfu/ml.
5. Take 1.0 ml aliquots of the inoculated product for
determination of viable count at 21 and 28 days.
6. Subject 1.0 ml aliquots removed at the specified time
intervals to a suitable series of decimal dilutions in
validated neutralizing media. Mix suspension well by
vortexing vigorously and incubate for a suitable period of
time to allow for neutralization.
If the antimicrobial agent(s) in the formulation cannot be
adequately inactivated or neutralized it may be eliminated
using a validated membrane filtration procedure (Micro--
Appendix D).
7. Determine the viable count of organisms in appropriate
dilutions by preparation of triplicate plates (unless
otherwise justified) of suitable recovery medium (e.g., TSA
for bacteria and SDA for mold and yeast). The agar for pour
plates should be kept between 40-50°C prior to pouring. The
agar media used for determination of viable counts may also
contain antimicrobial inactivators or neutralizers if
required. Where membrane filtration has been employed to
remove/neutralize antimicrobial agents, membranes should be
cultured on these media as appropriate.

` 92
8. Incubate bacterial recovery plates at 30-35°C for 2-4 days.
Incubate yeast at 20-25°C or 30-35°C for 3-5 days and mold
recovery plates at 20-25°C for 3-7 days.
9. Determine the average number of cfu on countable plates and
record. Countable plates refer to 30-300 cfu/plate for
bacteria and yeast, and 8-80 cfu/plate for mold except when
colonies are observed only for 100 or 10-1 dilution plates.
Calculate microbial reduction at the specified time points.
10. The concentration of survivors is calculated at each time
point. The concentration of viable organisms following the
14-day rechallenge is the sum of the rechallenge inoculum
concentration and the 14-day survivor concentration.
D. Controls
1. Inoculum Controls
The initial and rechallenge inoculum concentrations are
calculated by dispersing an identical aliquot of the
inoculum into the same volume of a suitable diluent (e.g.,
DPBST) as used in III.C.1 to achieve a final concentration
of 1.0 X 105 - l.0 X 106 cfu/ml for the initial inoculum or
1.0 X 104 - 1.0 X 105 cfu/ml for the rechallenge inoculum.
Ensure dispersion of the inoculum by adequate mixing. This
control sample should be evaluated within 1 hour of its
preparation using the same procedure used for the inoculated
product. This serves to demonstrate the suitability of the
medium used for growth of the test organism and provides an
estimate of the initial (rechallenge) inoculum
concentration.
2. Recovery Medium Control
Qualify the neutralizing agent/medium for the product
initially and periodically thereafter. Prepare a 1/10
dilution of the preserved product in the validated
neutralizing broth (1 ml into 9 ml). If a greater dilution
of the test solution is required to achieve neutralization,
the latter dilution should be used. Prepare a second
control tube with 10 ml of a suitable diluent (e.g., TSB).
Inoculate the tubes with sufficient inoculum to result in
10 - 100 cfu of challenge organism per plate. Incubate for
an appropriate period of time at ambient temperature. Plate
the appropriate aliquot from each tube onto the recovery
agar plates in triplicate unless otherwise justified. The
recovery in the neutralizer broth should be at least 50% of
the recovery in the second control tube. This control is to
be performed for each challenge organism.

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IV. PERFORMANCE CRITERIA
A. Bacteria
The number of organisms recovered per ml is reduced by a mean
value of not less than 3.0 logs at 14 days. After the rechallenge
at day 14, the concentration of bacteria should be reduced by at
least a mean value of 3.0 logs by day 28.
B. Molds and Yeasts
The number of organisms recovered per ml remain at or below the
initial concentrations within an experimental error of ±0.5 logs
within 14 days. At day 28, the concentration of mold and yeast
should remain at or below the concentrations after the rechallenge
within an experimental error of ±0.5 logs.
C. Products should be capable of meeting these criteria throughout
their labeled shelf-life.

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MICRO--APPENDIX B
DISINFECTION EFFICACY TESTING
PART 1. STAND-ALONE PROCEDURE FOR DISINFECTING PRODUCTS
I. PRINCIPLE
The stand-alone test challenges a disinfecting product with a standard
inoculum of a representative range of microorganisms and establishes the
extent of viability loss at pre-determined time intervals comparable with
those during which the product may be used. The size of the microbial
challenge chosen in this test is not intended to be representative of the
likely challenge in practice, but to provide countable numbers from which
estimation of the rate and extent of viability loss can be determined.
In carrying out the test for antimicrobial activity, the qualitative
composition of the product should be known at the time of testing by
either analytical testing or extrapolation.
Appropriate measures should be taken to inactivate or remove residual
antimicrobial agents during culturing and counting of survivors and the
effectiveness of these measures should be validated and the action of
this process during the test should be demonstrated by the construction
of suitable controls.
Three batches of product should be tested. Each batch of product should
be tested with a separate inoculum preparation for each challenge
organism.
II. MATERIALS AND REAGENTS
A. Test Organisms
Pseudomonas aeruginosa NCIMB 8626 ATCC 9027
Staphylococcus aureus NCTC 10788 ATCC 6538
Serratia marcescens NCTC 10211 ATCC 13880
Candida albicans NCTC 3179 ATCC 10231
Fusarium solani ATCC 36031
B. Test Media
Potato Dextrose Agar (PDA)
Tryptone Soya Broth (TSB)
Tryptone Soya Agar (TSA)
Sabouraud Dextrose Agar (SDA)
Dulbecco's Phosphate Buffered Saline without calcium chloride and
magnesium chloride (DPBS): 200 mg/L KCl, 200 mg/L KH2PO4,
8000 mg/L NaCl, and 2,160 mg/L Na2HPO4•7H20 or a suitable diluent.
Dulbecco's Phosphate Buffered Saline plus 0.05% w/v polysorbate 80
(DPBST) or a suitable diluent.
Validated neutralizing agents/media required (e.g., Dey-Engley
Neutralizing Broth and Agar).

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C. Test Equipment
Sterile pipettes, glass beads, swabs, tubes, 100 X 20 mm petri
dishes, etc., as required. Suitable instruments for
spectrophotometric determination of cell density, for colony
counting, and for centrifugation.
D. Test Samples
Product samples to be tested should be representative of the
product to be marketed. Aliquots should be taken directly from
the final product container immediately prior to testing.
III. TEST METHOD
A. Culture Maintenance
Cultures should be maintained in the manner recommended by the
curator of the appropriate culture collection. Cultures should be
no greater than five passes removed from the depository stock
(ATCC, NCIB, NCTC, NCPF or other recognized culture depository.)
B. Preparation of Microbial Challenge (Inoculum)
Test organisms should be cultured on agar as in Table 1.
Table 1
Media and Incubation Conditions for Growth of Challenge Organisms
Organism Medium Temp(0C) Incubation Time
P. aeruginosa TSA 30-35 18-24 hrs
S. aureus TSA 30-35 18-24 hrs
S. marcescens TSA 30-35 18-24 hrs
C. albicans SDA 20-25 42-48 hrs or
SDA 30-35 18-24 hrs
F. solani PDA 20-25 10-14 days
To harvest all cultures, use sterile DPBST or a suitable diluent,
washing the surface growth and transfer to a suitable vessel. The
spore suspensions may be filtered through sterile glass wool,
cotton gauze or cheese cloth to remove hyphal fragments.
After harvesting, the cultured organisms may be washed using
centrifugation. If centrifugation is used, each centrifugation
should be conducted at 2-25oC for no longer than 10 minutes at
4000 x g or less. The bacterial suspensions may be filtered
(e.g., 3 - 5 μm pore size) to produce a single cell dispersion.
All challenge cell suspensions should then be adjusted with DPBST
or other suitable diluent to 1 X 107 - 108 cfu/ml. The
approximate cell concentration may be estimated by measuring the
turbidity of the suspension or a dilution of the suspension using
a spectrophotometer. The actual concentration of cfu/ml should be
determined for each suspension by the plate count method at the
time of the test.

` 96
Bacterial and yeast cell suspensions should be used on the day of
preparation. Bacterial and yeast cell may lose viability and
resistance if not used on day of preparation. Spore suspensions
may be used up to 7 days following preparation by storage under
refrigeration (Avg. 4+20C).
C. Test Procedure
1. Prepare one tube containing a minimum of 10 ml of test
solution per challenge organism. Inoculate the sample tube
of the product to be tested with a suspension of test
organisms sufficient to provide a final count of 1.0 X 105 -
1.0 X 106 cfu/ml. The volume of inoculum should not exceed
1% of the sample volume. Ensure dispersion of the inoculum
by adequate mixing.
2. Store inoculated product at 20-250C. Temperature should be
monitored using a calibrated device and documented. If
sensitive to light the product should be protected during
the period of the test.
3. Take 1.0 ml aliquots of the inoculated product for
determination of viable count at 25%, 50%, 75% and 100% of
the minimum recommended disinfection time for all organisms,
and, in addition, at not less than 4 times the minimum
recommended disinfection time for yeast and mold. Where
overnight disinfection is recommended, disinfection time is
taken to be 8 hours.
4. Subject 1.0 ml aliquots removed at the specified time
intervals to a suitable series of decimal dilutions in
validated neutralizing media. Mix suspension well by
vortexing vigorously and incubate for a suitable period of
time to allow for neutralization.
If the antimicrobial agent(s) in the formulation cannot be
adequately inactivated or neutralized it may be eliminated
using a validated membrane filtration procedure (e.g.,
Micro--Appendix D).
5. Determine the viable count of organisms in appropriate
dilutions by preparation of triplicate plates (unless
otherwise justified) of a suitable recovery medium (e.g.,
TSA for bacteria and SDA for mold and yeast).
Where membrane filtration has been employed to
remove/neutralize antimicrobial agents, membranes should be
cultured on these media as appropriate. The agar for pour
plates should be kept between 40-500C prior to pouring. The
agar media used for determination of viable counts may also
contain antimicrobial inactivators or neutralizers if
required.
6. Incubate bacterial recovery plates at 30-350C for 2-4 days.
Incubate yeast at 20-250C or 30-350C for 3-5 days and mold
recovery plates at 20-250C for 3-7 days.

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7. Determine the average number of cfu on countable plates.
Countable plates refer to 30 to 300 cfu/plate for bacteria
and yeast, and 8 to 80 cfu/plate for mold except when
colonies are observed only for the 100 or 10-1 dilution
plates. Calculate microbial reduction at the specified time
points.
D. Controls
1. Inoculum Control
An inoculum count is made by dispersing an identical aliquot
of the inoculum into the same volume of suitable diluent
(e.g., DPBST) as used in Part 1:III.C.1 to achieve a final
concentration of 1.0 X 105 - 1.0 X 106 cfu/ml. The volume of
inoculum should not exceed 1% of the sample volume. Ensure
dispersion of the inoculum by adequate mixing. This control
sample should be evaluated for cfu/ml at the beginning of
the test. This serves to demonstrate the suitability of the
medium used for growth of the test organism and provides an
estimate of the initial inoculum concentration.
2. Recovery medium control
Prepare a 1/10 dilution of the disinfecting solution in the
validated neutralizing broth (1 ml into 9 ml). If a greater
dilution of the test solution is required to achieve
neutralization, the latter dilution should be used. Prepare
a second control tube with 10 ml of a suitable diluent
(e.g., TSB). Inoculate the tubes with sufficient inoculum
to result in 10-100 cfu of challenge organism per plate.
Incubate for an appropriate period of time at ambient
temperature. Plate the appropriate aliquot from each tube
onto the recovery agar plates in triplicate unless otherwise
justified.
The recovery in the neutralizer broth should be at least 50%
of the recovery in the second control tube. This control
should be performed for each challenge organism.
IV. PERFORMANCE REQUIREMENT
A. Control Specification
If any control value falls out of specification, the associated
test is invalid and should be repeated.
B. Primary Criteria (See Part 2, Table 2)
1. Bacteria
The number of organisms recovered per ml should be reduced
by a mean value of not less than 3.0 logs within the minimum
recommended disinfection period.

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2. Molds and Yeasts
The number of organisms recovered per ml should be reduced
by a mean value of not less than 1.0 log within the minimum
recommended disinfection time with no increase at not less
than four times the minimum recommended disinfection time.
C. Secondary Criteria (See Part 2, Table 2)
Products failing to meet the criteria in Part I:IV.B.1 or
Part 1:IV.B.2 may be evaluated by the regimen test procedure
described below, provided there is a combined log reduction for
the means of all bacteria of not less than 5.0 within the
recommended disinfection period. The minimum acceptable mean log
reduction for any single bacterial type is 1.0. Stasis for the
yeast and mold (within an experimental error of +0.5 log) should
be observed for the recommended disinfection period.

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PART 2. REGIMEN PROCEDURE FOR DISINFECTING REGIMENS
I. PRINCIPLE
This procedure is applicable to multi-functional disinfection regimens
which may include the steps of cleaning, rinsing, and soaking. In
carrying out the regimen test procedure, the products should be used in
the manner and quantity recommended in product labeling and/or patient
instructions. The test challenges the proposed disinfection regimen
with a standard inoculum of a representative range of microorganisms.
The inoculum is carried through the various stages of the regimen by
preliminary application to contact lenses.
The disinfecting stage of any proposed contact lens disinfection regimen
evaluated by this test should have demonstrated minimum antimicrobial
activity by the Stand-Alone Procedure as indicated for Regimen
Qualification.
In carrying out the test, qualitative and quantitative composition of
all products used in the test regimen should be known at the time of
testing, either by analytical testing or extrapolation.
Appropriate measures should be taken to inactivate or remove residual
antimicrobial agents during culturing and counting of the challenge
organism and the effectiveness of these measures should be demonstrated
by the construction of suitable controls.
A minimum of three lots of product should be tested. Each lot of
product should be tested with a separate inoculum preparation for each
challenge organism.
II. MATERIALS AND REAGENTS
A. Test Organisms
Pseudomonas aeruginosa NCIMB 8626 ATCC 9027
Staphylococcus aureus NCTC 10788 ATCC 6538
Serratia marcescens NCTC 10211 ATCC 13880
Candida albicans NCPF 3179 ATCC 10231
Fusarium solani ATCC 36031
B. Test Media
Tryptone Soya Broth (TSB)
Tryptone Soya Agar (TSA)
Sabouraud Dextrose Agar (SDA)
Potato-Dextrose Agar (PDA)
Dulbecco's Phosphate Buffered Saline without calcium chloride and
magnesium chloride (DPBS): 200 mg/L KCl, 200 mg/L KH2PO4,
8000 mg/L NaCl, and 2,160 mg/L Na2HPO4•7H20 or suitable diluent.
Dulbecco's Phosphate Buffered Saline plus 0.05% w/v polysorbate 80
(DPBST) or suitable diluent. Validated neutralizing agents/media
as required (e.g., Dey-Engley Neutralizing Broth and Agar).

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C. Test Equipment
Sterile pipettes, glass beads, swabs, tubes, filters, etc., as
required. Suitable instruments for spectrophotometric
determination of cell density, for colony counting, and for
centrifugation.
D. Test Samples
Test product samples to be tested should be representative of the
product to be marketed. Aliquots should be taken directly from
the final product container immediately prior to testing. All
regimen items, including cases, lenses, cleaning devices, etc.,
should be new and unused. If the test regimen results will be
directly compared with results for a predicate device, then a
predicate device from the same product category should be used for
the comparison (e.g., a hydrogen peroxide product should be
compared to a predicate hydrogen peroxide system and a multi-
purpose product should be compared to a predicate multi-purpose
product). Refer to Part 2:IV (PERFORMANCE REQUIREMENT).
III. TEST METHODS
A. Culture Maintenance
Cultures should be maintained in the manner recommended by the
curator of the appropriate culture collection. Cultures should be
no greater than 5 passes removed from the depository stock (ATCC,
NCIB, NCTC, NCPF or other recognized culture depository).
B. Preparation of Microbial Challenge (Inoculum)
Test organisms should be cultured and harvested as in
Part 1:III.B.
After harvesting, organic soil consisting of heat killed yeast
cells and heat inactivated serum, should be combined with the test
organism to result in an initial concentration of 1 X 107 - 108
cfu/ml.
Prepare organic soil as follows. Culture S. cerevisiae on SDA at
20-25°C for 48 hrs. Harvest as in Part 1:III.B. Heat kill the
suspension at 100 ±2°C for 10 minutes. Centrifuge at no more than
5000 X g for a maximum of 30 minutes. Resuspend in bovine serum
which has been heated at 56°C for 30 minutes to inactivate
complement. The concentration of S. cerevisiae in serum should be
1 X 107 - 108.
Centrifuge test organism suspension. Resuspend in organic soil to
a concentration 1 X 107 - 108 cfu/ml. This is the inoculum to be
used in the following procedure.

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C. Test Procedure
1. Lens Inoculation
The test should be conducted with lens types representative
of those with which the regimen is intended to be used
(e.g., low water non-ionic, high water ionic, silicone
acrylate, etc.).
Inoculate eight lenses per lot of test product per microbial
species tested; to qualify for all hydrophilic lenses use
four (4) non-ionic low water lenses and four (4) ionic high
water lenses. For hydrophobic lenses, use four (4)
silicone-acrylate and four (4) fluorosilicone-acrylate
lenses.
Organism 1 Hydrophilic Lenses
Group I Material Group IV Material
Lot 1 of Test Product 4 lenses 4 lenses
Lot 2 of Test Product 4 lenses 4 lenses
Lot 3 of Test Product 4 lenses 4 lenses
12 lenses 12 lenses
Organism 1 Hydrophobic Lenses
Silicone-Acrylate Fluorosilicone-
Acrylate
Lot 1 of Test Product 4 lenses 4 lenses
Lot 2 of Test Product 4 lenses 4 lenses
Lot 3 of Test Product 4 lenses 4 lenses
12 lenses 12 lenses
For hydrophilic or hydrophobic lenses, a total of 120 lenses
(24 for each organism/60 lenses in each representative lens
material) will be needed to test all 5 organisms.
Place test and control lenses, concave surface uppermost in
a sterile petri dish.
Inoculate each lens by placing 0.01 ml of inoculum on the
under surface of the lens at the point of contact between
the petri dish and the lens, and 0.01 ml of inoculum on the
top surface of the lens.
Allow the inoculum to absorb to each lens for 5-10 min. at
20-250C.
2. Lens Treatment
After inoculum absorption, treat lenses as described in the
manufacturer's consumer instructions for lens disinfection,
including all steps of cleaning, rinsing and soaking
specified by the manufacturer. Cleaning and rinsing

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procedures (e.g., rubbing and rinsing times and rinse
volumes) should be performed in identical fashion for the
predicate device and the test sample, unless otherwise
stated in the manufacturer's consumer instructions for lens
care. Test protocols should specify these parameters.
3. Recovery of Surviving Challenge Organisms (e.g., Micro--
Appendix D Membrane Filtration Procedure)
a. Dispense suitable volume of validated neutralizing
medium into filtration apparatus.
b. Transfer entire content of each test lens case (lens
and solution) into the neutralizing medium in the
filtration apparatus. The neutralization exposure
time prior to filtration should be determined in the
validation study.
c. Apply vacuum and filter solution. Rinse the filter
two additional times with the neutralizing medium.
d. Aseptically transfer the lens onto a bed of agar
medium appropriate for recovery of the test organism.
Pour 40-500C agar medium (same as bed agar above)
over the lens to cast it.
e. Apply the test filter to the surface of a plate of
appropriate solid media (could be the same as used in
Part 2:III.C.3.d).
f. Incubate bacterial recovery plates at 30-350C for 2-4
days. Incubate yeast recovery plates at 20-250C or
30-35oC for 3-5 days and mold recovery plates at 20-
25°C for 3-7 days.
D. Controls
1. Lens Inoculation Control
For each microbial species tested transfer 3 inoculated
lenses to tubes of TSB (for bacteria and yeasts) or SDB (for
fungi) as appropriate. Vortex for 30 seconds. Serially
dilute and plate out appropriate dilutions to permit a count
of viable cells present.
This count confirms that the number of organisms on the lens
at the time of regimen challenge is adequate. The mean of
the 3 counts should be not less than 2.0 X 105.

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2. Neutralization and Recovery Control
Prepare filtration apparatus in triplicate (unless otherwise
justified) as in Part 2:III.C.3 with suitable volumes of
neutralizing medium and disinfecting solution. Add 5 to 50
cfu of challenge organism, filter and cultivate as outlined
in Part 2:III.C.3.
Confirm inoculum on suitable medium in triplicate unless
otherwise justified.
The recovery in the neutralizer broth should be at least 50%
of the inoculum.
IV. PERFORMANCE REQUIREMENT
Bacteria, molds and yeast (See Table 2)
Less than or equal to 10 cfu recovered from each lens and test filter
combination for each test organism. Alternatively, the average number
of surviving organisms recovered on the lens and the respective test
filter should be shown to be substantially equivalent to results
obtained for the predicate device(s) when tested according to this
regimen procedure. Organism counts (average for each organism) may be
considered to be substantially equivalent if the difference between the
subject device and the predicate device is less than or equal to 0.5
log.

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Table 2
SUMMARY OF RECOMMENDED PERFORMANCE
CRITERIA FOR CONTACT LENS DISINFECTION PROCEDURES
MEAN LOG REDUCTION AT DISINFECTION TIME
PRODUCT FUNGI BACTERIA
FSa CA SM PA SA
Stand-Alone
Criteria
1 1 3 3 3
Regimen
Qualification
b b c c c
Regimen
Criteria
d d d d d
a FS = F. solani ATCC 36031,
CA = C. albicans ATCC 10231,
SM = S. marcescens ATCC 13880,
PA = P. aeruginosa ATCC 9027,
SA = S. aureus ATCC 6538
b Stasis with an experimental error of +0.5 log at the disinfection time.
c The minimum acceptable log reduction for the mean value of all 3
bacteria combined should be 5.0. The minimum acceptable log reduction
for any single bacterial type should be 1.0.
d Less than or equal to 10 cfu per lens and test filter combination from
0.01 ml of 1 X 107 to 1 X 108 inoculum OR
The average combined number of surviving organisms recovered on the lens
and the respective test filter must be shown to be substantially
equivalent to the predicate device(s).

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MICRO--APPENDIX C
BACTERIOSTASIS TEST
I. PRINCIPLE
Bacteriostasis testing is performed for multi-dose saline products which
do not contain conventional preservatives, yet do contain bacteriostatic
agents (e.g., borate, boric acid, potassium sorbate, and EDTA). For
these products, which do not meet the preservative efficacy criteria
described in Micro--Appendix A, a discard date should be determined on
the basis of the product's bacteriostatic activity. The bacteriostasis
test is a modification of the preservative efficacy test procedure.
Three lots of product should be tested. Each lot of product should be
tested with a separate inoculum preparation for each challenge organism.
II. MATERIALS & REAGENTS
A. Test Organisms
Pseudomonas aeruginosa NCIMB 8626 ATCC 9027
Staphylococcus aureus NCTC 10788 ATCC 6538
Escherichia coli NCIB 8245 ATCC 8739
Candida albicans NCPF 3179 ATCC 10231
Aspergillus niger IMI 149007 ATCC 16404
B. Test Media
Tryptone Soya Broth (TSB), Tryptone Soya Agar (TSA), Sabouraud
Dextrose Agar (SDA), Dulbecco's Phosphate Buffered Saline without
calcium chloride and magnesium chloride (DPBS): 200 mg/l KCl, 200
mg/l KH2PO4, 8000 mg/l NaCl, and 2,160 mg/l Na2HPO4•7H2O or suitable
diluent
Dulbecco's Phosphate Buffered Saline plus 0.05% w/v
polysorbate 80 (DPBST) or suitable diluent
Validated neutralizing agents/media as required (e.g., Dey-
Engley Neutralizing Broth and Agar).
C. Test Equipment
Sterile pipettes, glass beads, swabs, tubes, 100 X 20 mm petri
dishes, etc., as required. Suitable instruments for
spectrophotometric determination of cell density, for colony
counting, and for centrifugation.
D. Test Samples
Product samples to be tested should be representative of the
product to be marketed. Prepare one tube containing a minimum of
10 ml of test solution per challenge organism. The largest
container size proposed for the product should be used.

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III. TEST METHOD
A. Culture Maintenance
Cultures should be maintained in the manner recommended by the
curator of the appropriate culture collection. Cultures should be
no greater than 5 passes removed from the depository stock (ATCC,
NCIB, NCTC, NCPF or other recognized culture depository).
B. Preparation of Microbial Challenge (Inoculum)
Test organisms should be cultured on agar as in Table 1.
Table 1: Media & Incubation Conditions for Growth of
Challenge Organisms
Organism Medium Incubation
Temp oC Time
Pseudomonas aeruginosa TSA 30-35 18-24h
Staphylococcus aureus TSA 30-35 18-24h
Escherichia coli TSA 30-35 18-24h
Candida albicans SDA
SDA 20-25 42-48 or
30-35 18-24h
Aspergillus niger SDA 20-25 7 days
To harvest all cultures, use sterile DPBST or a suitable diluent,
washing the surface growth and transfer to a suitable vessel. The
spore suspensions may be filtered through sterile glass wool,
cotton gauze or cheese cloth to remove hyphal fragments.
After harvesting, the cultured organisms may be washed using
centrifugation. If centrifugation is used, each centrifugation
should be conducted at 2-25°C for no longer than 10 minutes at
4000 x g or less. The bacterial suspensions may be filtered
(e.g., 3 - 5 μm pore size) to produce a single cell dispersion.
All challenge cell suspensions should then be adjusted with DPBST
or other suitable diluent to 1 X 107 - 1 X 108 cfu/ml or cell
concentration sufficient to result in final concentration of 1 X
105 - 1 X 106 cfu/ml in the product. The approximate cell
concentration may be estimated by measuring the turbidity of the
suspension or a dilution of the suspension using a
spectrophotometer. The actual concentration of cfu/ml should be
determined for each suspension by the plate count method at the
time of the test.
Bacterial and yeast cell suspensions should be used on the day of
preparation. Bacterial and yeast cells may lose viability and
resistance if not used on the day of preparation. Spore
suspensions may be used up to 7 days following preparation by
storage under refrigeration (Avg. 4+2°C).

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C. Test Procedure
1. Inoculate the sample product to be tested with a suspension
of test organisms sufficient to provide a final count of 1.0
X 105 - 1.0 X 106 cfu/ml. The volume of inoculum should not
exceed 1% of the sample volume. Ensure dispersion of the
inoculum by adequate mixing.
2. Store inoculated product at 20-25°C. Temperature should be
monitored using a calibrated device and documented. If
sensitive to light the product should be protected during
the period of the test.
3. Take 1.0 ml aliquots of the inoculated product for
determination of viable count at 7, 14, 21, and 28 days. If
longer discard dates are desired, continue sampling
periodically thereafter.
4. Subject 1.0 ml aliquots removed at the specified time
intervals to a suitable series of decimal dilutions in
validated neutralizing media. Mix suspension well by
vortexing vigorously and incubate for a suitable period of
time to allow for neutralization.
If the antimicrobial agent(s) in the formulation cannot be
adequately inactivated or neutralized it may be eliminated
using a validated membrane filtration procedure (e.g.,
Micro-Appendix D).
5. Determine the viable count of organisms in appropriate
dilutions by preparation of triplicate plates (unless
otherwise justified) of suitable recovery medium (e.g., TSA
for bacteria and SDA for mold and yeast). The agar for pour
plates should be kept between 40-50°C prior to pouring. The
agar media used for determination of viable counts may also
contain antimicrobial inactivators or neutralizers if
required. Where membrane filtration has been employed to
remove/neutralize antimicrobial agents, membranes should be
cultured on these media as appropriate.
6. Incubate bacterial recovery plates at 30-35°C for 2-4 days.
Incubate yeast at 20-25°C or 30-35°C for 3-5 days and mold
recovery plates at 20-25°C for 3-7 days.
7. Determine the average number of cfu on countable plates and
record. Countable plates refer to 30-300 cfu/plate for
bacteria and yeast, and 8-80 cfu/plate for mold except when
colonies are observed only for 100 or 10-1 dilution plates.
Calculate microbial reduction at the specified time points.
8. The concentration of survivors should be calculated at each
time point.

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D. Controls
1. Inoculum Controls
The initial inoculum concentration should be calculated by
dispersing an identical aliquot of the inoculum into the
same volume of a suitable diluent (e.g., DPBST) as used in
III.C.1 to achieve a final concentration of 1.0 X 105 -
l.0 X 106 cfu/ml. Ensure dispersion of the inoculum by
adequate mixing. This control sample should be evaluated at
the same time as the zero time sample. This serves to
demonstrate the suitability of the medium used for growth of
the test organism and provides an estimate of the initial
inoculum concentration.
2. Recovery Medium Control
Qualify the neutralizing agent/medium for the product
initially and periodically thereafter. Prepare a 1/10
dilution of the product in the validated neutralizing broth
(1 ml into 9 ml). If a greater dilution of the test
solution is required to achieve neutralization, the latter
dilution should be used. Prepare a second control tube with
10 ml of a suitable diluent (e.g., TSB). Inoculate the
tubes with sufficient inoculum to result in 10 - 100 cfu of
challenge organism per plate. Incubate for an appropriate
period of time at ambient temperature. Plate the
appropriate aliquot from each tube onto the recovery agar
plates in triplicate unless otherwise justified. The
recovery in the neutralizer broth should be at least 50% of
the recovery in the second control tube. This control is to
be performed for each challenge organism.
IV. PERFORMANCE CRITERIA
A. Bacteria
The concentration of each bacterial challenge organism
should remain at the initial level or decrease.
B. Molds and Yeasts
The concentration of the yeast and mold should remain at
initial levels or decrease within an experimental error of
+0.5 log.
C. The product should be labeled to discard the container after
it has been opened for the number of days which corresponds
to time point previous to the point at which any organism
shows an increase in number (see example). The container
label should include a space on which to record the date
opened.

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Example:
(Concentration in Abbreviated Log Value)
DAY
0 7 14 21 28 35
E. coli 105 103 <10 101 102 103
P. aeru. 105 103 103 102 103 104
S. aureus 105 <10 <10 <10 <10 <10
C. alb. 105 105 104 102 <10 <10
A. niger 105 104 103 104 104 105
Cut off point: E. coli 14 days
P. aeru. 21 days
A. niger 14 days
The use of the above hypothetical product is limited to 14
days after opening.

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MICRO--APPENDIX D
MEMBRANE FILTRATION PROCEDURE
I. SUMMARY
This document provides an example of procedures and controls for
membrane filtration.
II. MATERIALS AND REAGENTS
A. Test Media
Suitable diluent with or without neutralizers
Tryptone Soya Agar (TSA)
Sabouraud Dextrose Agar (SDA)
Dulbecco's Phosphate Buffered Saline without calcium chloride and
magnesium chloride (DPBS): 200 mg/L KCl, 200 mg/L KH2PO4,
8000 mg/L NaCl, and 2,160 mg/L Na2HPO4•7H20 or other suitable
diluent
Dulbecco's Phosphate Buffered Saline plus 0.05% w/v polysorbate 80
(DPBST)
B. Test Equipment
Sterile pipettes, petri dishes, containers, etc., as needed.
Suitable sterile apparatus for holding the sterile membrane filter
and the filtrate. Suitable equipment for creating a vacuum or
pressure to cause the liquid phase of the inoculated test solution
to pass through the membrane filter aseptically. The membrane
filter should have a nominal pore size of not greater than
0.45 μm, a diameter of at least 47 mm and should be free of
chemicals which could be toxic to microbial cells.
III. TEST METHOD
A. Moisten the sterile membrane filter in a sterile filter assembly
with sterile DPBST or other suitable diluent.
B. Aseptically transfer a measured volume of the inoculated test
solution into sterile DPBST or other suitable diluent.
C. Transfer the diluted solution to the membrane and filter
immediately with the aid of vacuum or pressure. The sample
applied to the filter should be diluted in 50-100 ml of dilution
fluid and thoroughly mixed to ensure uniform distribution of the
sample over the entire area of the filter. This will decrease the
probability of multiple cfu being placed on the filter at the same
location.
D. Wash the membrane filter with several volumes of a suitable
diluent which may contain additional neutralizing agents as
needed. Three volumes of a suitable diluent (100 ml each) are
usually sufficient to remove and/or dilute the antimicrobial
agent. The actual volume should be determined empirically for
each formulation for each challenge organism.

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E. The membrane filter is then aseptically incubated with appropriate
media to allow growth of cfu on the surface of the filter. This
may be accomplished by aseptic removal of the membrane filter from
the filter assembly unit and placement of the membrane on the
surface of a sterile agar plate which does not have obvious liquid
on the surface or the membrane may be enclosed in an agar
sandwich. Alternatively, a sterile membrane filter unit may be
used which requires addition of sterile media to the sealed filter
and incubation of the membrane in situ. Media should be used
which are appropriate for the type of challenge organism and the
specific formulation under test.
F. Determine the average number of cfu on countable membrane filters
(3-100 cfu/47 mm filter for bacteria and yeast and 3-10 cfu/47 mm
filter for molds). Calculate the cfu/ml of inoculated solution.
G. Controls
Neutralizer efficacy may be confirmed by transferring an aliquot
of the uninoculated test solution into 50-100 ml of sterile
diluting fluid using the same ratio of volume of test solution to
volume of diluting fluid. Apply the entire volume to the membrane
and filter using vacuum or pressure. Wash the filter with several
volumes of the diluting fluid using the same volume as used for
the test procedure. Transfer 10-20 cfu for bacteria and yeasts or
3-10 cfu for molds into 100 ml of diluting fluid and apply to the
membrane. Incubate the membrane filter in contact with media as
described in the test procedure (see section III.E).
The procedure should be repeated using diluting fluid not exposed
to the test solution. Counts should be compared with those
derived by the same method but using DPBST instead of test
solution. The count observed for diluting fluid with test
solution should be comparable with that obtained for diluting
fluid. The latter count should be statistically comparable with a
direct plate count on rich medium to eliminate the possibility of
loss of viable cells by filtration or test medium toxicity.

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TOXICOLOGY
TABLE OF CONTENTS
Page
I. Introduction ..................................................113
II. Minimum Recommended Toxicology Test Procedures for Contact Lens
Care Products [i.e., Salines, Cleaners (Daily and Periodic),
Chemical Disinfecting Products for Contact Lenses Including
Neutralizing Solutions, and In-Eye Contact Lens Solutions
(Lubricating and/or Rewetting Drops)] .........................114
III. Additional Recommended Tests for Lens Care
Products ......................................................115
IV. Toxicology Tests for Containers................................115
V. Acute Oral Toxicity ...........................................116

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TOX--APPENDIX A
TOXICOLOGY
I. Introduction
This section of the guidance document discusses the toxicological
considerations that CDRH believes should be addressed in order to assess
substantial equivalence in terms of safety and biocompatibility of
contact lens care products.
In an effort to harmonize the biological response to testing of medical
devices, CDRH has issued blue book memorandum #G95-1 entitled "Use of
International Standard ISO-10993, "Biological Evaluation of Medical
Devices Part-1: Evaluation and Testing," which includes an FDA-modified
matrix that delineates the type of testing recommended for various
medical devices. It also includes a flow chart entitled
"Biocompatibility Flow Chart for the Selection of Toxicity Tests for
510(k)s." The tests recommended in this toxicology section are
generally consistent with the studies recommended in the blue book
memorandum but have been adapted for specific use with contact lens care
products.
The manufacturing process and chemical formulation used to fabricate a
contact lens/lens care product should dictate, in general, the extent of
the toxicology testing necessary to establish substantial equivalence in
terms of its safety and effectiveness. It is the applicant's
responsibility to develop an appropriate toxicology and biocompatibility
profile for the specific lens material/lens care product in order to
demonstrate that the device is substantially equivalent in terms of
safety and effectiveness to the predicate device. Any test suggested in
this toxicology section may be replaced by a suitable alternative if the
alternative test has been validated or can be justified for use as an
alternative. All nonclinical laboratory studies should include a
statement that each study was conducted in compliance with the GLP
Regulation for Nonclinical Laboratory Studies. If the study was not
conducted in compliance with the GLP Regulation, a justification of the
noncompliance should be submitted.
CDRH is aware of the ongoing research efforts to achieve the goal of
eventual substitution of in vitro tests for certain biological tests
utilizing animals*. However, at present, in vitro alternatives to
animal testing have not been sufficiently developed or validated for
use. Therefore, CDRH regrets that toxicology tests involving
animals will continue to be used at this time in order to adequately
assess risks and evaluate safety of ocular products prior to 510(k)
clearance. CDRH will continue to monitor the developments of
alternatives to animal testing and will recommend their use once such
studies have been validated.
___
*Goldberg, A.M., et al. Framework for Validation and Implementation of In
Vitro Toxicity Test: Report of the Validation and Technology Transfer
Committee of the Johns Hopkins Center for Alternatives to Animal Testing. J.
Am. Coll. Tox. 1993: 12:23-30.

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The toxicology studies recommended below are generally consistent with
the applicable studies recommended in normative standards and/or
USP/NF 23.
NOTE: In addition to the recommended tests listed, CDRH believes that
the material safety data sheet (MSDS) should be submitted in order to
establish a toxicology profile for active ingredients and/or new
chemical components incorporated into the finished contact lens care
product (i.e., preservative, tablet, etc.). CDRH is aware that
additional safety and toxicology data are generally included in the MSDS
which can be obtained from the supplier of the chemical constituent, in
lieu of performing additional or repetitive toxicology testing. The
MSDS should be included in the 510(k) submission.
II. Minimum Recommended Toxicology Test Procedures for Contact Lens Care
Products (i.e., Solutions/Tablets)
A. In-Vitro Cytotoxicity, USP/NF 23
The purpose of this study is to evaluate the potential for
toxicity of residual chemicals leaching from the lens into the
care products (i.e., solution(s)/solubilized tablets). In
addition, this test may be used to detect potential toxic
carryover from uptake/release of the solution by the lens. The
effects are assessed in vitro using cytotoxicity studies (i.e.,
Tissue Culture-Agar Diffusion Test, Direct Contact Test and/or
Elution Test) or a suitable validated alternative method.
B. Acute Ocular Irritation, USP/NF XXII
The purpose of the study is to evaluate the potential for ocular
irritation resulting from residual chemical leachables from the
finished device which may be extracted in the care products (i.e.,
solution(s)/solubilized tablets). This method is also used to
detect the potential for ocular irritation due to carryover from
uptake/release of the solution by the lens and from direct
instillation of an in-eye solution. This test should not be
needed in cases where formulations contain known ocular irritants.
In such cases, an appropriate warning should be required on the
label for products known to cause ocular irritation (i.e., daily
cleaners/periodic cleaners) in lieu of performing this test.
C. Acute Oral Toxicity
The purpose of this study is to assess the potential of the
contact lens care product (i.e., solution(s)/tablet(s)) to produce
a toxic response as a result of deliberate or accidental ingestion
of the device by adults or children. These data will be used to
determine the need for additional warnings or precautions in the
labeling of the product for the purpose of consumer protection.
For rodent testing, the maximum volume of an aqueous solution
generally should not exceed 2 ml/100 g body weight. This single
large dose is referred to as the maximum tolerable dose (MTD).
However, should signs of toxicity be demonstrated at this MTD,

` 115
further testing consistent with accepted toxicological practices
is recommended in order for CDRH to complete its risk/benefit
assessment of the device. See Tox--Appendix B for the suggested
test method.
III. Additional Recommended Testing
Data from the following tests should be submitted if a manufacturer is
using a new preservative or an active ingredient/chemical component not
previously used in a currently marketed contact lens care product.
A. Sensitization (Guinea Pig Maximization Test*):
The purpose of this test is to grade or rank chemical constituents
on a scale of I through V as to their potential for inducing
sensitivity response in the guinea pig model. The grades of
rankings are based on the number of animals sensitized, and
results are classified on an ascending scale from a weak
sensitizing agent (grade I) to an extreme sensitizing agent
(grade V).
___
*Magnusson, B. and Kligman, A.M. The Identification of Contact
Allergens by Animal Assay. The Guinea Pig Maximization Test. J.
Invest. Dermatol. 1969; 52.
B. In-Vivo Ocular Biocompatibility (ISO 9394-1994):
This test method entitled, "Optics and optical instruments--
Determination of biological compatibility of contact lens material
--Testing of the contact lens system by ocular study with rabbit
eyes," is published as an international standard by ISO. This ISO
standard has been evaluated by CDRH, and we believe it should be
acceptable in its entirety to address preclinical ocular
biocompatibility of contact lens products.
IV. Toxicology Tests for Containers
The purpose of these testing requirements is to indirectly or
directly assess the potential toxicity of constituent(s)
that may leach from the container when the solution comes in
contact with the container for a prolonged period of time. The
following in vitro and in vivo test procedures are recommended by CDRH
and are consistent with the procedures listed in USP/NF XXII, Containers
for Ophthalmics--Plastics (Biological Test Procedures).
A. Systemic Injection Test, USP/NF XXII
B. Acute Ocular Irritation
C. In-Vitro Cytotoxicity

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TOX--APPENDIX B
ACUTE ORAL TOXICITY
The following is a generalized test protocol that may be used as guidance in
assessing a contact lens solution for acute oral toxicity. Specific test
procedures may vary for each individual laboratory but generally should follow
the outline given below.
Purpose of the Study:
The objective of the study is to evaluate the potential oral toxicity of a
designated test material following a single oral dose at 15 g/kg of body
weight.
This study should be conducted in accordance with the requirements of the Good
Laboratory Practice (GLP) Regulations (21 CFR 58).
Control Article:
No control article should be employed in this study, since dose response
during the study may serve as an internal control.
Test System and Justification:
Ten albino rats of the Sprague-Dawley strain (five male, five female),
obtained from a commercial supplier, should be selected from the stock colony
after a minimum 5-day acclimation period. Prior to overnight food
deprivation, animal weights should range from 200 to 300 g. Rats should be
identified by ear punch and housed, according to sex, up to five per suspended
cage.
The rat has been historically used to establish relative LD50 data. The oral
route of dosing is selected as the strongest challenge for materials that
could be accidentally ingested. A 15 g/kg dose is generally regarded as
nontoxic (Gleason, et al, 1969).
Animal Management:
Animal husbandry and environmental conditions should conform to specifications
based on the "Guide for the Care and Use of Laboratory Animals," National
Institutes of Health (NIH) Publication No. 85-23. Rats should receive a
commercial rodent food on a daily basis; tap water should be freely available.
No contaminants are suspected to be present in the food or water that would
affect the results of this study.
No sedation, analgesia or anesthesia should be necessary in this procedure.
In the unlikely event that an animal should become injured, ill, or moribund,
euthanasia or veterinary care should be conducted in accordance with current
veterinary medical practice.

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Test Article Preparation:
Density (g/ml) of the liquid should be determined prior to dosing.
As far as practical, composition of the test substance should be known.
Information should include the name and quantities of all major components,
known contaminants and impurities, and the percentage of unidentifiable
materials to account for 100% of the test substance. Ideally, the lot of the
substances tested should be the same throughout the study. The test sample
should be stored under conditions that maintain its stability, strength,
quality, and purity from the date of its productions until the tests are
complete.
Methods and Route of Administration:
Food should be withheld overnight (16-20 hours). Each rat should then be
gavaged with a single 15 g/kg dose of the test material via stainless steel
blunt tipped cannula attached to a disposable syringe. The maximum dose
volume should not exceed 2 ml/100 g body weight. The rats should be weighed
at dosing, at observation day 7, and at day 14 of the study. Animals should
be observed for clinical signs of toxicity immediately after dosing, at 4
hours after dosing and daily for 14 days. Food should be returned following
the immediate observation. Rats found dead during the study and those
euthanatized should be subjected to a macroscopic examination of the viscera.
A complete gross necropsy should be performed on all animals that die during
the course of the study.
Evaluations and Statistics:
Mean body weights should be calculated for all animals at dosing (day 0) and
for survivors at days 7 and 14. Statistical manipulation of data is not
applicable to this study.
Should 80% of the animals survive, the test material preparation should not be
considered orally toxic. Greater than 20% mortality may warrant additional
investigation.
Report:
The report should contain a description of the methods employed, data
accumulated in tabular form and a summary of results.
Quality Assurance:
Inspections should be conducted at the major phases of the study (e.g., test
article preparation, dosing, and necropsy). The final report should also be
inspected for conformance to Subpart J of the GLP Regulations (21 CFR 58.185).
A Certificate of Quality Assurance Inspections should be provided with the
final report.

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Records:
Test article preparation, animal weights, observations for adverse clinical
signs, macroscopic necropsy findings, and dates of relevant activities (e.g.,
study initiation and completion) should be recorded.
All raw data pertaining to this study and a copy of the final report should be
retained in the designated archive files of the testing laboratory/sponsor.
References:
21 CFR 58 (GLP Regulations)
Gleason, M.N., et al. 1969. Clinical Toxicology of Commercial Products (Third
Ed.). The Williams & Wilkins Co., Baltimore, MD.

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CLIN--APPENDIX A
CLINICAL
I. Introduction:
This section of the guidance is designed to assist manufacturers in
developing clinical performance data necessary to demonstrate
substantial equivalence to a class II lens care product. Whenever
possible, CDRH has provided manufacturers with guidance on when to
submit clinical performance data and recommended minimum numbers for the
size and duration of a clinical study for a new or modified lens care
product. When clinical performance data are needed, however, it is the
overall responsibility of the manufacturer to design the clinical study
with an appropriate number of subjects and sufficient duration to
provide adequate data to demonstrate substantial equivalence.
The means for collecting clinical performance data should be designed
and conducted in a manner that will provide data constituting valid
scientific evidence within the meaning of 21 CFR 860.7. It is not
merely a compilation of available subject records. Monitoring of the
study, accountability of all subjects, and details of complications or
discontinuations are all essential elements.
It is important to note that while CDRH has recommended the appropriate
use of controlled studies, such as randomized controlled trials, as a
means of minimizing study biases, it also recognizes that some devices
with well documented clinical experience may be studied with no control
group. This will allow the sponsor to gain experience with the use of
the device as well as to confirm safety as predicted from the
preclinical data developed for the device.
The recommended preclinical testing is heavily weighted toward
demonstrating substantial equivalency to a predicate device. The
clinical testing is generally considered as additional confirmatory
information to supplement the preclinical data. This is particularly
true for "me-too" types of products which are within the marketed
concentrations for the active ingredients of the predicate device.
Study protocol suggestions are provided in Clin--Appendix B. It is
recommended that the study involve evaluable (completed) subjects
divided evenly between independent investigators when applicable. In
order to maximize the subjects' exposure to the products during the
clinical study, a daily wear schedule should be followed for most
products. However, a study of a periodic cleaner, used on weekly
intervals, may provide more valuable clinical data concerning efficacy
when extended wear subjects are enrolled than a similar study with daily
wear subjects.
Clinical study designs may take on a variety of appearances. Concurrent
control groups either of equal number to the test group, or utilizing an
approximate 2:1 ratio of test to control subject ratio (see table 1) are
but two examples. A cross-over study design may also be appropriate in
some cases. The use of intrapatient controls in a solution study may

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not be feasible for some products, but may be utilized if the sponsor
desires and determines it to be appropriate.
Historical data may also serve as a control for products with available
literature information, or from a manufacturer's previous clinical
database, when an adequate justification is provided. If historical
controls are used instead of interpatient controls, the historical
control group should be defined and adequately characterized for
comparison to the test group. When literature information is utilized,
a review of applicable published studies along with comparative analysis
of the study design, subject populations and outcome measures should be
provided. Simply citing references would not be appropriate as a
control.
For a clinical study of hydrophilic lenses, the study may be designed
with subjects divided as equally as possible between Group I and Group
IV lenses. Subjects in clinical studies with RGP lenses should be
divided as equally as possible between RGP lens groups requested for
510(k) clearance (currently there are four). If the manufacturer of a
lens care solution wishes to recommend its use with a specific type of
lens in the labeling, the compatibility with the lens type should be
confirmed preclinically and/or during the clinical trial.
Any lens care product study resulting in more than one adverse reaction
should include adequate justification in order to establish substantial
equivalence to the predicate device in terms of safety and
effectiveness. The clinical sample sizes are calculated to be
reasonably assured of obtaining at least one complication, as a function
of the expected complication rate (5% for a 60 subject group, 10% with a
30 subject group), with a probability of greater than 95%. Therefore,
in a subject group of 30 evaluable (completed) subjects exposed to a
short term duration of a test product, an adverse event occurrence in 2
to 3 subjects will raise questions as to biocompatibility and
fundamental safety of the product.
The clinical protocol for non-significant risk studies requires IRB
clearance prior to beginning the study. Applicants should provide the
complete protocol along with the study report in their application. FDA
recommends the protocol study design, at a minimum, address the
following:
1. Statement of the specific study objective(s)
2. Study duration
3. Sample size and selection criteria
4. Number of investigators and selection criteria
5. Methods of reducing study biases (control, etc.)
6. Study materials (lenses and care regimen)
7. Follow-up visit schedule

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8. Methods of data collection, monitoring, and analysis
When questions remain concerning the protocol or content and format of a
510(k), sponsors should consult with DOD prior to finalizing their
clinical protocol and initiating the investigation.
A “Modified” Trend Analysis Profile (TAP) form should be completed for
all clinical studies and included in the clinical report section of the
510(k). The TAP helps identify trends in clinical data which assist the
manufacturer and CDRH reviewers in evaluating the substantial
equivalence of a device to a legally marketed device. This equivalence
is based on whether any differences between the devices would affect
safety and effectiveness.
Note that in small clinical studies of short duration (i.e., 30 subjects
for 1 month duration), the TAP in addition to a written summary of the
clinical trial results may be considered as sufficient documentation for
submission. More extensive clinical study submissions should be
supported by a TAP as well as a complete clinical report to include the
summary reporting tables (Clin--Appendix D).
A sample TAP form is available in Clin--Appendix E. The sample form
establishes the basic format that should be presented; however, it
should be expanded to include all slit lamp parameters measured as well
as visual acuity results and lens replacements. This is especially
important when the TAP is provided for the short duration studies
without the summary reporting tables. Sponsors with questions
concerning the TAP should contact DOD staff for clarification.
Table 1
Example of Distribution of Completed Subjects for Hydrophilic Lens
Study with 2:1 Ratio of Test to Control
60-Subject Study
Lens Material Test Group Control Group Total
Group IV 20 10 30
Group I 20 10 30
Subtotal 40 20 60
30-Subject Study
Lens Material Test Group Control Group Total
Group IV 10 5 15
Group I 10 5 15
Subtotal 20 10 30

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CLINICAL TESTING MATRIX FOR CLASS II CONTACT LENS CARE PRODUCTS
Product Same Active
Ingredients Within
Marketed
Concentrations
Same Active
Ingredients In
Higher
Concentrations Than
Marketed Products
Same Active
Ingredients in Lower
Concentrations Than
Marketed Products
New Ingredients For
Ophthalmic Use or
Different Active
Ingredient
Saline
Solutions
60 subj/1 mo
Daily Cleaner Footnote A Footnote B 60 subj/3 mo
Periodic
Cleaner
Footnote A 30 subj/1 mo 60 subj/3 mo
Soaking
Solution for
Disinfection
30 subj/1 mo 60 subj/3 mo
Neutralizer 30 subj/1 mo Footnote A 60 subj/3 mo
Conditioning
Solution 30 subj/1 mo 60 subj/3 mo
In-Eye
Solution 30 subj/1 mo 30 subj/1 mo 30 subj/1 mo 60 subj/3 mo
Footnote A: Clinical performance data may need to be submitted depending on
the physical/chemical, microbiological and toxicological data collected (i.e.,
a higher concentration of the active cleaning ingredient in a multi-purpose
solution may require submission of clinical data while an increase in
concentration of the active ingredient in a periodic cleaner may not unless it
is used in conjunction with the disinfection regimen). If necessary, a 30
subject/1 month study should be conducted.
Footnote B: If active ingredient is a surfactant, the sponsor may use either
appropriate in vitro tests or conduct a clinical test with 60 subjects/3
months to establish the efficacy of the lower concentration of active
ingredient.
In the absence of validated in vitro data, such as non-surfactant cleaning
studies, at present a cross-over design with additional in-vitro analysis of
worn lenses is an example of one method to demonstrate substantial equivalence
to the predicate device. While it may not always be necessary to consult with
DOD prior to developing a test protocol, sponsors should note that additional
discussion and guidance will be provided if requested.
II. Necessity for Clinical Performance Data and Study Size and Duration
Recommendations:
A. Claim of Substantial Equivalence for a Lens Care Product Based
Upon Same Active Ingredients:

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1. Claims of substantial equivalence for a lens care product
based upon the same active and inactive ingredients within
marketed concentrations and the same manufacturing processes
will not need clinical performance data provided that the
preclinical testing (i.e., physical/chemical,
microbiological and toxicological data) supports the claim.
This pertains to an identical "me-too" product for the same
product specific intended use and indication as the
predicate device. In some cases, the applicant may have
obtained referencing rights to predicate device data.
2. Claims of substantial equivalence for a lens care product
based upon the same active ingredients within marketed
concentrations but different inactive ingredients in some
cases require clinical performance data, in addition to
physical/chemical, microbiological and toxicological data,
to support the claim. This "me-too" product may not be
identical to the predicate device since the inactive
ingredients in the predicate device may not be identified.
If any of preclinical characteristics differ from the
predicate device (data outside the range of the test method)
the sponsor should justify why this characteristic
difference will not impact upon the safety and effectiveness
or supply supporting clinical performance data.
When clinical performance data are necessary, such as for
in-eye solutions, it is recommended that this study involve
at least thirty (30) evaluable subjects followed for at
least 1 month.
3. Claim of substantial equivalence based upon same active
ingredients in higher or lower concentrations than marketed
products generally require clinical performance data to be
submitted depending on the physical/chemical,
microbiological and toxicological data collected to support
the claim.
When clinical performance data are necessary it is
recommended that this study involve at least 30 evaluable
subjects followed for at least 1 month.
B. Claim of Substantial Equivalence for a Lens Care Product with New
Ingredients for Ophthalmic Use or Different Active Ingredient:
Claims of substantial equivalence for a lens care product with new
ingredients for ophthalmic use or different active ingredient
require submission of clinical performance data, in addition to
physical/chemical, microbiological and toxicological data, to
support the claims. It is recommended that this clinical study
involve at least sixty (60) evaluable (completed) subjects
followed for at least 3 months.

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C. Labeling Claims with Additional Indications:
The sponsor should design the study to collect data demonstrating
the substantial equivalence of the lens care product to a legally
marketed device in terms of the safety and effectiveness of the
device. Additional indications could include use of the product
with a different lens material [e.g., rigid gas permeable lenses
(hydrophobic) when previously indicated for soft hydrophilic
lenses, or an additional product specific intended use such as
saline solution repackaged and relabeled as a rewetting drop].
Applicants should select an appropriate predicate device for
comparisons and determination of substantial equivalence. The
appropriate clinical testing matrix for the additional claim(s)
should be referred to for guidance. Applicants may also contact
DOD prior to initiating studies if they have questions.
III. Study Summary
For the purpose of ease in the submission of clinical performance data
in support of a claim of substantial equivalence, DOD recommends that
the following outline be utilized:
A. Introduction
1. Purpose
2. Statement of compliance
3. List of investigators to include number of eyes enrolled by
each; control and trial, completed and discontinued
B. Materials and Methods
1. Study materials; to include lens(es) utilized and any
solutions in addition to the study solution for both test
and control subjects
2. Study design and procedures; to include randomization
procedures, if utilized
3. Data analysis
C. Subjects
1. Demographic data
2. Completed and discontinued for both control and trial groups
D. Data to support substantial equivalence - sample tables included
in Clin--Appendix D (data for control eyes should be reported
separately from data for the trial eyes)
1. Adverse Reactions
2. Slit Lamp Examination
3. Symptoms/Problems/Complaints
4. Visual Acuity
5. Average Wear Time
6. Discontinued Eyes
7. Lens Replacements

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Note: Keratometric changes and refractive changes have been
deleted as any event severe enough to cause these types of changes
in experienced lens wearers would manifest itself in other
categories
E. “Modified” Trend Analysis Profile - Clin--Appendix E
F. Conclusion

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CLIN--APPENDIX B
CLINICAL PROTOCOL SUGGESTIONS
OUTLINE
I. ALL STUDY DESIGNS
II. LENS CARE PRODUCT STUDIES
A. PROTOCOL CONSIDERATIONS
1. Statement of Specific Study Objective(s)
2. Sample Size and Study Duration
3. Sample Selection Criteria (a-e)
4. Investigator Selection Criteria
5. Methods of Study Control
6. Adjunct Solutions
7. Visit Schedule
a. General Information
b. Follow-up Schedules
8. Monitoring and Accountability
a. Enrollment/Accountability
b. Visit Forms
c. Monitoring Responsibilities
d. Methods of Analysis
B. METHODS OF DATA COLLECTION AND ANALYSIS
1. Adverse Reaction Data
2. Slit Lamp Findings
3. Symptoms/Problems/Complaints
4. Visual Acuity
5. Average Wear Time
6. Discontinuation
7. Lens Replacements
III. PROBLEMS/QUESTIONS

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I. ALL STUDY DESIGNS:
It is important that the means for collecting clinical performance
data be designed and conducted in a manner that will provide data
constituting valid scientific evidence within the meaning of 21 CFR
860.7. In that section, the essentials of a well-controlled clinical
investigation are discussed. During the design of a study the impact
of the protocol on final product labeling should be kept in mind.
II. LENS CARE PRODUCT STUDIES:
A. Protocol Considerations:
The clinical protocol should, at a minimum, address the
following:
1. Statement of the Specific Study Objective(s)
2. Sample Size (interpatient controls) and Study Duration--
is dependent upon the basis for the claim of substantial
equivalence and formulation.
a. At least 60 evaluable subjects (one evaluable
subject is defined as two completed eyes) for a
minimum of 3 months for a claim of substantial
equivalence based upon the same intended use, but
composed of new ingredients for ophthalmic use or
different active ingredient.
b. At least 30 evaluable subjects for a minimum of 1
month for a claim of substantial equivalence based
upon the same intended use, composed of the same
active ingredients as the predicate product, a "me-
too" product (refer to matrix).
3. Sample Selection Criteria
The following definitions should be used when reading
this section.
Normal: a set of clinical findings which would not
prevent a subject from contact lens wear. For example, a
small corneal scar located off the visual axis which is
long-standing may not preclude the use of cosmetic
contact lenses.
Abnormal: a finding which would preclude a subject from
consideration as an acceptable lens candidate.
a. Subjects should have worn contact lenses
successfully previously (so as to not add another
variable to the study).

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b. Subject selection for entry into the study should
meet the entry criteria established in the
protocol.
c. In appropriately randomized, controlled studies,
the subjects should be randomly assigned to either
the control or the test group and the sponsor
should detail the randomization procedure.
d. Subjects should have normal eyes and use no ocular
medications. A normal eye is defined as having the
following characteristics:
(1) no anterior segment infection, inflammation
or abnormality;
(2) no other active ocular or systemic disease
that would contraindicate contact lens wear;
and
(3) no medications that would contraindicate
contact lens wear.
e. Subjects with normal eyes not correctable to 20/40
with spectacles may be enrolled, but should be
analyzed separately.
A minor positive finding should not disqualify a subject
from participating in a clinical study if the
investigator determines that the finding does not
interfere with contact lens wear or cause the eye to
become compromised from contact lens wear. The
investigator should use clinical judgment to determine a
subject's eligibility based on any trace pre-fitting
observations and the study protocol as designed by the
monitor and sponsor.
4. Investigator Selection Criteria
The sponsor should select an appropriate number of
investigators to minimize biases. The training,
experience, and objectivity of investigators should also
be considered when attempting to reduce study biases.
As an example, a ratio of evenly assigning enough
subjects to each investigator to allow for an evaluation
of trends between investigators would be two (2) or three
(3) investigators for a 30 subject study, and three (3)
or four (4) investigators in a 60 subject study. The
targeted minimum number of subjects per site would then
be 10 to 15 in a small study, and 15 to 20 in the large
study. These numbers also allow for the poolability of
data for analysis.

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5. Methods of Study Control
The sponsor should address those features of the study
design which have been devised to minimize biases. CDRH
suggests protocols which incorporate the appropriate use
of controlled studies as a means of minimizing biases in
clinical data. Randomized controlled clinical trials
(RCT) may be appropriate in some cases, but not in all
cases, refer to the Introduction section of Clinical
(Clin--Appendix A). If the sponsor chooses to use
historical controls instead of interpatient controls, the
historical control group should be defined and adequately
characterized for comparison to the test group.
For further information refer to texts such as:
Friedman, L.M. et al. Fundamentals of Clinical Trials.
John Wright-PSG Inc., Boston, MA, 1982.
Meinert, C.L. and S. Tonascia. Clinical Trials - Design,
Conduct and Analysis. Oxford University Press, New York,
NY 1986.
6. Adjunct Solutions
All lens care products used in the study should be
specified. The surface quality of the lenses should also
be assessed for such findings as deposits, cracking or
crazing. CDRH recommends the use of grading systems to
standardize such findings. One example of a grading
system for deposits is the modified Rudko Method which is
discussed in an article by R.A. Hathaway and G.E. Lowther
in the Journal of the American Optometric Association, 49
(3) 259-266, 1978.
Another grading scale is as follows:
Lens Surface Characteristics
Front Surface Wettability:
0 = a smooth uniformly reflecting surface
1 = a coarse hazy surface which seems resolved
momentarily with each blink and becomes
exacerbated with staring
2 = a stable dry (non-wetting) area of some magnitude
3 = gross crystalline or amorphous deposits

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Front Surface Deposits:
0 = absent, clean surface
1 = very slight, only visible after tear film drying
2 = slight, visible deposits easily removed
3 = moderate, deposits adherent and not removable
4 = severe, non-removable deposits and comfort affected
Findings of an increase in the frequency of use for
lubricants, in-office cleanings, or need for enzyme use
should be evaluated and addressed by the applicant.
7. Visit Schedule
a. General Information
All subjects in a study should be on the same
follow-up schedule. In the event an ocular
abnormality is observed at any visit, the
investigator should see the subject as frequently
thereafter as necessary to treat and eliminate the
abnormality. (Documentation of abnormalities will
be discussed later.) The reason for each
unscheduled visit should be reported in the 510(k).
b. Follow-up Schedules (after the initial dispensing
of new lenses and lens care products)
The following schedule contains target dates,
rather than absolute dates for follow-up. In most
cases, the sponsor may assign acceptable windows
around each target date to further clarify the
visit schedule for the investigator:
One Month Study: 1 week, 2 weeks, 4 weeks.
Three Month Study: 1 week, 4 week, then monthly
through study.
Any subject reporting for an unscheduled visit
should be documented on the reporting tables under
"Unscheduled Visit."
8. Monitoring and Accountability
(Reference 21 CFR 812 Subparts C and E)
a. Enrollment/Accountability
A subject should be considered enrolled when he or
she signs the informed consent form. This form
should be signed prior to dispensing of any lens
care products. All subjects enrolled should be
accounted for even if they are not dispensed lens
care products. Once enrolled, a subject is
considered "active" and should be accounted for at
every visit until completion of, or discontinuation
from, the study.

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b. Visit Forms
A visit form should be filled out and signed by the
investigator performing the examination at the time
of the scheduled or unscheduled visit. Adverse
reaction reports must be completed in accordance
with 21 CFR 812.46(b) and submitted to CDRH.
c. Monitoring Responsibilities
If an investigator is not complying with the signed
agreement, the investigational plan or other
conditions imposed by the IRB or CDRH, the sponsor
should either secure compliance or discontinue
shipments of the device to the investigator and end
his or her participation in the study.
d. Methods of Analysis
The sponsor should summarize the methods of
analysis including any appropriate statistical
methods of evaluating the data.
B. Methods of Data Collection and Analysis:
This section discusses the data which are provided to support
the claim of substantial equivalence. The Summary Reporting
Tables (Clin-Appendix D) may be used by sponsors as a basis for
developing clinical reporting forms.
1. Adverse Reaction Data
CDRH believes an "adverse reaction" would include, but
not be limited to a hazardous, sight-threatening
condition such as: corneal ulcers, severe corneal
abrasion > 2 mm in diameter, iritis, other ocular
infections or inflammations, corneal scarring, or
permanent loss of vision.
Photodocumentation or detailed drawings that detail the
size, location and depth of the adverse reaction should
be provided. Infections should be cultured.
The sponsor should detail the events of all adverse
reactions including all treatment(s) and diagnoses
through the resolution of the event.
Events which are not sight-threatening should be graded
and reported as significant findings in the appropriate
category such as slit lamp findings or the
symptoms/problems/complaint section.

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Non-sight-threatening events may include, but are not
limited to, the following: giant papillary
conjunctivitis, epiphora, dry eyes, and irritation.
2. Slit Lamp Findings
Slit lamp examinations should be performed at each visit.
The investigator should record all positive and negative
(grade 0) findings, not only those which are considered
to be clinically significant. The results should be
tabulated, and all findings over grade 2 should be
explained in the 510(k).
An example of a SLIT LAMP FINDINGS CLASSIFICATION SCALE
is included in Clin--Appendix C. Other suitable well
defined classification scales can be found in the FDA
PREMARKET NOTIFICATION (510(k)) GUIDANCE DOCUMENT FOR
DAILY WEAR CONTACT LENSES or the ISO standard, Optics and
Optical Instruments - Contact Lens and Contact Lens Care
Products - Guidelines for Clinical Investigations,
ISO/DIS 11980.
3. Symptoms/Problems/Complaints
Subjective data should be collected at each visit and
tabulated in the 510(k). These data are used in
conjunction with objective findings in the assessment of
safety and effectiveness.
Additionally, the following information may be submitted:
Subjective Acceptance
Below are samples of acceptable grading scales for a
limited number of parameters. Please refer to Table 5 of
Clin--Appendix D, Informative Summary Reporting Tables,
for additional sample parameters.
Other suitable well defined scales, such as that found in
the ISO standard, Optics and Optical Instruments -
Contact Lens and Contact Lens Care Products - Guidelines
for Clinical Investigations, ISO/DIS 11980, may also be
used. Sponsors may also consider utilizing an
alternative to the numeric rating scale, such as a visual
analog scale, provided the method is appropriate for
collection and analysis of the data.

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Comfort:
0 = Excellent, cannot be felt
1 = Very comfortable, just felt occasionally
2 = Comfortable, noticeable but not irritating
3 = Slightly uncomfortable, just irritating or annoying
4 = Very uncomfortable, very irritating or annoying
5 = Causes pain, lens cannot be tolerated
Vision:
0 = Excellent, cannot notice any visual loss
1 = Very good, just noticeable and very occasional
reduction
2 = Good, occasional noticeable but acceptable reduction
3 = Poor, noticeable but acceptable reduction
4 = Very poor, marked and unacceptable reduction
5 = Unacceptable, lens cannot be worn
Handling:
0 = excellent, no problems with lens insertion and
removal
1 = Very good, occasional difficulty with lens
insertion and removal
2 = Good, some problems but insertion and removal
usually successful
3 = Poor, difficult and very occasional unsuccessful
insertion/removal
4 = Very poor, difficult and occasional unsuccessful
insertion/removal
5 = Unmanageable, lenses impossible to handle
4. Visual Acuity (VA) Data
Distance VA should be taken at each visit. Although
other acceptable scales such as Snellen Acuity are
available, the use of logMAR progression VA charts with
equal steps between successive lines is recommended.
For purposes of submission, the initial VA (best
corrected with the contact lens) should be compared to
the VA results with the contact lens at the final visit.
VA decreases of 2 or more lines should be reported with
explanations. Investigator comments and explanations for
all decreases of 2 or more lines at final visit compared
to initial visit should be included. Additionally, a
similar decrease in VA during the course of the study
should be reported and explained.
5. Average Wear Time (AWT)
The lens AWT should be recorded at each visit. A
tabulated report of AWT in hours, or days as appropriate,
by visit should be provided to assess trends during the

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study. When data are collected for both daily lens
wearers and extended lens wearers, these data should be
analyzed separately.
6. Discontinuations
Complete data should be provided on all discontinued
subjects including the reason for discontinuation and
visual status at the final visit. If problems persist,
the subject should be followed until resolution of the
problem. All data which would normally be collected at
the final study visit should also be collected at the
discontinued subject's last visit. Copies of subject
report forms for all discontinued subjects should be
provided in the submission.
7. Lens Replacements
The reason for each replacement should be tabulated in a
manner which allows for trend analysis during the course
of the study. Lens replacements for the following
reasons should be further explained: discoloration,
response to physiological problems, slit lamp findings,
or "other."
III. PROBLEMS/QUESTIONS:
When questions remain concerning the protocol or content and
format of a 510(k), sponsors should consult with DOD prior to
finalizing their clinical protocol and initiating the
investigation.

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CLIN--APPENDIX C
SLIT LAMP FINDINGS CLASSIFICATION SCALE
A. EDEMA
Corneal edema should be classified according to the haziness of the
epithelium, the number of microcysts observed, and the clouding of the
stroma.
EPITHELIAL EDEMA
0 - NONE: None: No epithelial or sub-epithelial haziness. Normal
transparency
1 - TRACE: Barely discernible localized epithelial or subepithelial
haziness
2 - MILD: Faint but definite localized or generalized haziness
3 - MODERATE: Significant localized or generalized haziness
4 - SEVERE: Definite widespread, epithelial cloudiness giving dull
glass appearance to cornea, or numerous coalescent bullae
(Note the number and location of bullae)
EPITHELIAL MICROCYSTS
0 - NONE: No microcysts
1 - TRACE: 1 to 20 microcysts
2 - MILD: 21 to 50 microcysts
3 - MODERATE: 51 to 100 microcysts
4 - SEVERE: > 100 microcysts or bullae
The presence/absence of vacuole or bullae should be documented along with
their numbers. The presence of bullae should be considered as reportable
grade 4 severe epithelial edema.
STROMAL EDEMA
0 - NONE: None: No stromal cloudiness. Normal transparency
1 - TRACE: Barely discernible localized stromal cloudiness
2 - MILD: Faint but definite localized or generalized stromal
cloudiness
3 - MODERATE: Significant localized or generalized stromal cloudiness
4 - SEVERE: Definite widespread, stromal cloudiness, or numerous
striae. (Note the number and location of striae)
B. CORNEAL NEOVASCULARIZATION
Maximal corneal vascularization should be reported according to the
following scale:
0 - NONE: No vessel penetration
1 - TRACE: < 1.0 mm vessel penetration
2 - MILD: 1.0 mm - 1.5 mm vessel penetration
3 - MODERATE: 1.5 mm - 2.0 mm vessel penetration
4 - SEVERE: Vessel penetration > 2.0 mm.

O p t i o n a l l y t h e dept-h and l o c a t i o n of v e s s e l p e n e t r a t i o n can a l s o be
r e p o r t e d as f o l l o w s :
Depth
a . 	super£ i c i a l
b . 	s t r o m a l
L o c a t i o n
N 	N a s a l 	T 	Temporal
I 	I n f e r i o r 	S 	S u p e r i o r
C 	C i r c u m f e r e n t i a l 	X 	Other 	( d e s c r i b e )
C . 	CORNEAL S T A I N I N G
It i s recommended t h a t sponsors d e s i g n d a t a c o l l e c t i o n forms t o o b t a i n
i n f n n n a c i o n concerning ehc location of corneal staining so tAlat p e r i p h e r a l
s t a i n i n g can be d i f f e r e n t i a t e d from c e n t r a l s t a i n i n g .
Maximal c o r n e a l s t a i n i n g s h o u l d h~ r ~ r n r d ~ d	accnrding to the following
scale :
2 - MILD:
3 - MODERATE:
4 - SEVERE:
0 - NONE: 	No s t a i n i n g
1 - TRACE: 	Minimal s u p e r f i c i a l s t a i n i n g o r s t i p p l i n g
a . 	Dimpling, d i s c r e t e d o t s t a i n i n g , OR
b . 	Trace s u p e r f i c i a l l e n s i n s e r t i o n marks o r
f o r e i g n body t r a c k s
Regional o r d i f f u s e p u n c t a t e s t a i n i n g
a . 	C e n t r a l o r g e n e r a l i z e d , OR
b . 	P e r i p h e r a l including 3 9 o'clock staining, OR
c . Mild a b r a s i o n o r f o r e i g n body t r a c k s
Dense c o a l e s c e d s t a i n i n g up t o 2 m d i a m e t e r
a . Corneal a b r a s i o n
b . 	Foreign body track
Dense c o a l e s c e n t s t a i n i n g g r e a t e r t h a n 2 mm i n d i a m e t e r
o r f u l l t h i c k n e s s a b r a s i o n ,
L o c a t i o n : 	N - N a s a l , T 	- Temporal, 	I - I n f e r i o r , 	S - 	S u p e r i o r ,
C - C e n t r a l

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D. BULBAR HYPEREMIA
Maximal limbal and bulbar hyperemia should each be recorded on a 5
point scale as follows:
0 - NONE: No hyperemia present
1 - TRACE: Slight regional hyperemia
2 - MILD: Diffuse hyperemia
3 - MODERATE: Marked regional or diffuse hyperemia
4 - SEVERE: Diffuse episcleral or scleral hyperemia
E. PALPEBRAL CONJUNCTIVAL OBSERVATIONS
The location of maximal conjunctival response should be documented
according to the following scale:
0 - NONE: Uniform satin appearance of conjunctiva
1 - TRACE: Slight conjunctival injection without texture
2 - MILD: Mild or scattered papillae/follicles less than 1 mm in
diameter
3 - MODERATE: a. Significant papillae/follicles less than 1 mm in
diameter, and/or marked conjunctival injection
b. Staining of the top of one papilla
4 - SEVERE: a. Localized or generalized papillae/follicles 1 mm
or more in diameter
b. Staining of the top of more than 1 papilla
Optionally, the conjunctival response can also be recorded for each
of the four lid areas:
Upper lid
1 - Superior tarsal conjunctiva
2 - Middle tarsal conjunctiva
3 - Inferior (lid margin region) tarsal conjunctiva
Lower lid
4 - Palpebral conjunctiva of lower lid
F. OTHER COMPLICATIONS (List all reports by specific finding and grade by
severity)
This section is intended to capture less commonly observed clinical
entities such as corneal infiltrates, conjunctival infection, EKC, corneal
ulcers, iritis, lens adhesions and recurrent erosion. The complication
should be identified and described according to the following generic
scale.

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Example provided for infiltrates, but the concept is applicable to all
findings:
0 - NONE: No other significant biomicroscopic findings
1 - TRACE: Minimal finding such as one faint peripheral infiltrate
which does not stain
2 - MILD: Mild findings such as a few faint infiltrates
3 - MODERATE: Significant findings such as multiple, dense infiltrates
4 - SEVERE: Severe finding such as marked infiltrates with overlying
staining

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CLIN--APPENDIX D
INFORMATIVE SUMMARY REPORTING TABLES
(Provided for reference)
Table 1 Notes:
TITLE: Accountability of Eyes Enrolled and Distribution by Status
PURPOSE: To ensure a complete accounting of all eyes enrolled in the
investigation.
General: Six status subgroups are identified and defined below. In all cases
status is as of the cutoff date of the study at which time data were tabulated
for submission.
Enrolled Dispensed: All subjects who signed an informed consent form
prior to having lens care product(s) dispensed to them.
Completed Eyes: Eyes which used the lens care product(s) for the
prescribed investigational period and for which a final visit form was
completed and submitted.
Active Eyes: Eyes which were using the lens care product(s) but had not
completed the prescribed investigational period.
Discontinued Eyes: Eyes which had ceased using the lens care product(s)
prior to completion of the prescribed investigational period.
Incomplete Eyes: Eyes which have completed the prescribed investigation
period but for which a final visit report has not been received by the
sponsor.
Enrolled But Not Dispensed: Eyes considered enrolled because the
subject had signed an informed consent form, but for which lens care
product(s) had not been dispensed.

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TABLE 1
ACCOUNTABILITY BY EYES ENROLLED IN THE STUDY
AND DISTRIBUTION BY STATUS
Status Number of Eyes
____________________________ ____________________________
Enrolled Dispensed
Completed C/T
Active (Visit Completed)
Dispensing C/T
1st follow up C/T
2nd follow up C/T
(list through) nth follow up C/T
Total Active C/T
Discontinued C/T
Incomplete C/T
Total Dispensed C/T
Enrolled Not Dispensed C/T
Total Enrolled C/T
C = # control eyes
T = # trial eyes

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Table 2 Notes:
TITLE: Demographics
PURPOSE: To provide demographic data.
TABLE 2
DEMOGRAPHICS
Age of Subjects: From _____ To _____, Average _____.
Sex: Female _____, Male _____, Ratio _____.

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Table 3 Notes:
TITLE: Adverse Reactions (3A), SLFs Requiring Treatment (3B), SPCs Requiring
Treatment (3C)
PURPOSE: To provide a detailed accounting of any condition occurring in any
eye in the study requiring treatment to ensure ocular health.
DEFINITIONS:
Adverse Reaction: Considered to include, but not be limited to a hazardous,
sight-threatening condition such as: corneal ulcers, iritis, other ocular
infections or inflammations, corneal scarring, or permanent loss of vision.
SLFs Requiring Treatment: Any slit lamp finding in any examination,
scheduled or unscheduled, that requires treatment, including temporary
discontinuation of lens wear, to maintain normal ocular health. This does
not include SLFs that are corrected by refitting of lenses without
discontinuation of wear or by retraining subjects in proper lens care.
SPCs Requiring Treatment: Any symptom, problem or complaint that requires
treatment, including temporary discontinuation of lens wear, to maintain
normal ocular health. This does not include SPCs that are corrected by
refitting of lenses without discontinuation of wear or by retraining of
subjects in proper lens care.
GENERAL: Outcome should include cause of condition, treatment required,
resolution including VA, damage to the eye if any, and whether or not
discontinued from the study.

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TABLE 3
ADVERSE REACTIONS (3A)
ADVERSE TIME IN
REACTION INVESTIGATION OUTCOME
_____________________________________________________________________________
1.
2.
3.
4.
etc.
Total eyes with adverse reactions____.
______________________________________________________________________________
SLFs Requiring Treatment (3B)
SLF TIME IN
INVESTIGATION OUTCOME
__________________________________________________________________________
1.
2.
3.
4.
etc.
Total eyes with SLFs requiring treatment _____.
___________________________________________________________________________
SPCs Requiring Treatment (3C)
SPC TIME IN
INVESTIGATION OUTCOME
1.
2.
3.
4.
etc.
Total eyes with SPCs requiring treatment____.
______________________________________________________________________________

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Table 4 Notes:
TITLE: Slit Lamp Findings By Visit, Tabulated By Eyes and Incidence Rate
PURPOSE: To provide comprehensive tabulation of SLF data by visit (time in
study) and completeness of recording.
GENERAL:
Separate tables should be prepared and clearly identified for:
Completed Control Eyes (Table 4A)
Completed Trial Eyes (Table 4B)
Discontinued Control Eyes (Table 4C)
Discontinued Trial Eyes (Table 4D)
In Tables 4A and 4B, total eyes should be the same for all visits and the same
as the number of eyes completed in Table 1.
In Tables 4C and 4D, total eyes will vary by visit as a function of when
subjects discontinued.
Intermediate visits should be numbered in sequence and the time in study for
each sequence number should be provided in a footnote to Table 4A.
Tables 4 (A, B, C & D) should be expanded laterally as necessary to provide a
data column for each intermediate visit.
For each SLF (e.g., edema, vascularization, etc.) a horizontal row should be
provided for each SLF grade up through the highest grade recorded for each
SLF.
Slit Lamp Findings reported between scheduled visits should be reported under
"Unscheduled Visits."
Percentages should be calculated in accordance with the following formula:
# = Eyes at grade of SLF or eyes not recorded
% = Incidence rate or percent eyes not recorded
% Incidence Rate = Eyes at grade of SLF
Total Eyes at visit X 100
% Eyes not recorded = Eyes not recorded
Total eyes at visit X 100
Any SLFs that require treatment should be listed in Table 3B.
In the "Eyes Not Recorded" row, list the number of eyes and percent not
recorded for each visit.

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TABLE 4
SLIT LAMP FINDINGS BY VISIT, TABULATED BY EYES
AND INCIDENCE RATE
Initial Intermediate Visits
Dispensing
Visit 1 2 3 4 Unsched. Total
# % # % # % # % # % # % # %
(Parameters reported should correspond to grading scale used in the study)
EDEMA
grade 0 X X
grade 1 X X
grade 2 X X
grade 3 X X
grade 4 X X
NEOVASCULARIZATION
grade 0 X X
grade 1 X X
grade 2 X X
grade 3 X X
grade 4 X X
STAINING
grade 0 X X
grade 1 X X
grade 2 X X
grade 3 X X
grade 4 X X
OTHER
grade 0 X X
grade 1 X X
grade 2 X X
grade 3 X X
grade 4 X X
(Include all parameters assessed in study)
Eyes not recorded X X
Total eyes XX XX XX XX XX XX XX

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Table 5 Notes:
TITLE: Symptoms, Problems, and Complaints by Visit, Tabulated by Eyes and
Incidence Rates
PURPOSE: To provide comprehensive tabulation of data on SPC by visit (time in
study).
GENERAL:
Separate tables should be prepared and clearly identified for:
Completed Control Eyes (Table 5A)
Completed Trial Eyes (Table 5B)
Discontinued Control Eyes (Table 5C)
Discontinued Trial Eyes (Table 5D)
In Tables 5A and 5B, total eyes should be the same for all visits and the same
as the number of "eyes completed" in Table 1.
In Tables 5C and 5D, total eyes will vary by visit as a function of when
subjects discontinued.
Intermediate visits should be numbered in sequence and the time in study for
each sequence number should be provided in a footnote to Table 5A.
Tables 5 (A, B, C & D) should be expanded laterally as necessary to provide a
data column for each intermediate visit.
SPCs reported between scheduled visits should be reported under "Unscheduled
Visits."
Percentages should be calculated in accordance with the following formula:
# = Eyes reporting that SPC
% = Incidence rate at visit
% Incidence Rate = Eyes reporting SPC at final visit
Total eyes at final visit X 100
Any SPCs that require treatment should be listed in Table 3C.

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TABLE 5
SYMPTOMS, PROBLEMS, AND COMPLAINTS BY VISIT
TABULATED BY EYES AND INCIDENCE RATES
Initial Intermediate Visits Total
Dispensing
Visit 1 2 3 4 Unscheduled
Total Eyes XX XX XX XX XX XX XX
At Visit
# % # % # % # % # % # % # %
__________________________________________________________________________
None X X X X X X XX
(The following are examples of parameters assessed. Some may not be
applicable for a given study design)
Discomfort
Excess Tearing
Photophobia
Halos
Itching
Burning
Spectacle Blur
Variable Vision
Blurred Vision
Lens Needs
Cleaning
Lens Awareness
Other (Specify)
Total X X X X X X XX
Positive Reports

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Table 6 Notes:
TITLE: Visual Acuity (VA) Results with Contact Lens at Final Visit
PURPOSE: To provide VA data for the contact lens in a concise format.
GENERAL:
Separate tables should be prepared and clearly identified for:
Completed Control Eyes (Table 6A)
Completed Trial Eyes (Table 6B)
Discontinued Control Eyes (Table 6C)
Discontinued Trial Eyes (Table 6D)
In addition to the data on the table for the final visit, the data in the
"Visual Acuity Summary" should be provided. The number of eyes that had a VA
of 2 or more lines on the logMAR progression scale worse than the initial best
corrected VA should be provided for each visit, and an explanation should be
provided for each instance in the second section of Table 6.
Number and percentage in each horizontal row of each VA column refer to the
number of eyes in the best corrected column for the corresponding row.
Percentage should be calculated in accordance with the formula on the table.

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TABLE 6
VISUAL ACUITY RESULTS WITH CONTACT LENS
AT FINAL VISIT (EXAMPLE PROVIDED IN logMAR NOTATION
Initial Number Not
Best of -0.1 0.0 0.1 0.2 0.3 . . . Reported Totals
Corrected Eyes # % # % # % # % # % # % # %
-0.1 X X X X X X
0.0 X X X X X X
0.1 X X X X X X
0.2 X X X X X X
0.3 X X X X X X
(Continue
as Needed) X X X X X X
Totals X X X X X X
# of eyes at each VA (or total)
% at each VA = # of eyes at initial best x 100
(or total) corrected of corresponding row
Visual Acuity Summary:
# eyes with initial best corrected VA of 0.2 logMAR or better _____.
# eyes with final VA with lens of 0.2 logMAR or better _____.
# eyes with final VA with lens within +/- 1 logMAR progression of best
corrected _____.
# eyes with final VA with lens of worse than +/- 1 logMAR progression of best
corrected _____.

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TABLE 6 (cont.)
LISTING OF EYES THAT CHANGED 2 OR MORE LINES ON THE
VISUAL ACUITY SCALE
Initial VA at
Investigator Subject Eye VA Visit Reason
1.
2.
3.
etc.

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Table 7 Notes:
TITLE: Average Wear Time per Visit
PURPOSE: To provide an accounting of wearing time by time in study.
GENERAL:
Separate tables should be prepared and clearly identified for:
Completed Control Eyes (Table 7A)
Completed Trial Eyes (Table 7B)
Discontinued Control Eyes (Table 7C)
Discontinued Trial Eyes (Table 7D)
Number and percentage refer to the number of eyes in the average wearing time
column for the corresponding row. Percentage should be calculated in
accordance with the following formula:
% at each time = # of eyes at each time
# of total eyes x 100

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TABLE 7
AVERAGE WEAR TIME
Intermediate Visits Final
1 2 3 4 Unscheduled Visit
Wearing time
# % # % # % # % # % # %
0 to 6.0 X X X X X X
6.1 to 12.0
12.1 to 18.0
1 overnight
2 overnights
3 overnights
4 overnights
5 overnights
6 overnights
Not reported
Wearing time
average/visit

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Table 8 Notes:
TITLE: Discontinued Eyes Tabulated by Completed Visits and Reasons for
Discontinued with Incidence Rates
PURPOSE: To provide comprehensive data on all discontinued eyes with reasons
for discontinuation, time in study, and incidence rates.
GENERAL:
Eyes known to have discontinued between scheduled visits should be listed in
the "Unscheduled Visits" column.
Total discontinuations should be provided for each intermediate visit.
Aggregate discontinuations and aggregate incidence rate should be calculated
for each reason and for total discontinuations.
Aggregate incidence rates should be calculated in accordance with the formula
shown on the table. It is recognized that this formula will result in some
error because active and incomplete eyes are not taken into account. However,
this error will be small unless the discontinuation rate, number of active
eyes, or number of incomplete eyes is excessive. In such cases, submission of
additional data and subsequent review may be required.
Note: More than one reason may be given for discontinuation. In such a case,
note only the principal reason on the table and identify the additional
reasons in a footnote to the table.

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TABLE 8
DISCONTINUED EYES TABULATED BY COMPLETED VISITS
AND REASONS FOR DISCONTINUED WITH INCIDENCE RATES
Eyes at (or after) Visit Completed
Reasons for Intermediate Aggre.
Discontinuation INITIAL 1 2 3 4 Unsch. Disc. %
Visual acuity
Positive SLF
Adverse Reaction
Lens Positioning
Discomfort
Handling Problem
Disinterest
Lost-to-Follow-up
None Given
Other (Specify)
Total
% Incidence = Aggregate eyes discontinued per reason
Total eyes completed + total eyes disc. x 100
C = # control eyes
T = # trial eyes

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Table 9 Notes:
TITLE: Lens Replacements by Visit
PURPOSE: To provide a tabulation of all lenses replaced during the study by
reason for replacement.
GENERAL:
Separate tables should be prepared and clearly identified for:
Completed Subjects (Table 9A)
Discontinued Subjects (Table 9B)
Lenses replaced for visual acuity, pathology or other physiological reasons
must be listed individually, with the specific reason for replacement and the
visual acuity with the replacement lens.
Number and percentage refer to the number of eyes for each reason for
replacement for the corresponding row. Percentage should be calculated in
accordance with the following formula:
% of eyes with lenses replaced = # of eyes at each visit
# of total eyes x 100

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TABLE 9
LENS REPLACEMENTS BY VISIT
Reason for Intermediate Visit
Replacement INITIAL 1 2 3 4 Unsched.
Total
# % # % # % # % # % # % # %
Visual Acuity C/T C/T C/T C/T C/T C/T C/T
Comfort
Pathology
Base Curve
Diameter
Lost
Torn
Lens Deposits
Bad Edge
Bad Surface
Discoloration
Other (Specify)
Totals C/T C/T C/T C/T C/T C/T C/T
C = # control eyes
T = # trial eyes

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CLIN--APPENDIX E
“MODIFIED” TREND ANALYSIS PROFILE
The “Modified” Trend Analysis Profile (TAP) is intended to assist in the
identification of trends. The TAP provides the number of events (e.g.,
adverse reactions), that occur at each visit of the study as well as the total
number of events occurring during the study. In a sense, it is similar to a
life table analysis in that it may quickly indicate the interval of time from
the entry of subjects into the trial until the occurrence of specific events
(e.g., adverse reactions). It may also reveal data trends that would be
difficult to glean from the clinical report; however, it is not intended to
replace the clinical report or a 510(k) Summary of Safety and Effectiveness.
The following directions outline the appropriate methods recommended for
completing the TAP form. CDRH anticipates that the TAP form may evolve over
time as CDRH and sponsors discover improved means of presenting trend data.
Item Category Instructions for completing TAP
1 Time in Study This entry identifies how far the study has
progressed (e.g., 1 week or 1 month into the
study). (The data reported in a given column
should represent only the data collected
during that particular time interval. Only
data in the Total column, at the far right of
the table, are cumulative for the entire
study.)
2 Total # of Eyes This number includes the total number of
eyes, either active or discontinued, that
were examined during that time interval.
3 D/C Eyes This number includes all the eyes
discontinued during that time interval.
4 Average Wear Time This number is the average wear time reported
by all eyes, either active or discontinued,
during that time interval.
5 Lens Replacements This number is the actual number of lenses
replaced during that time interval.
6 All Adverse Reactions Each adverse reaction should be recorded only
at the onset of the event. Follow-up visits
for that particular event should not be
recorded here.
7 All Corneal Ulcers This is a subset of the Adverse Reactions
discussed in Item 5. For this entry, each
ulcer should be recorded only at the onset in
the same manner that adverse reactions were
reported in Item 5.

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8 All Iritis This is a subset of the Adverse Reactions
discussed in Item 5. For this entry, each
iritis episode should be recorded only at the
onset in the same manner that adverse
reactions were reported in Item 5.
9 Total Reports Staining This number includes all staining reports
which occurred during that time interval. If
there are multiple reports for one eye, each
report should be counted in this category.
10 Staining Reports >Gr 2 This number includes all staining reports
greater than grade 2, which occurred during
that time interval. If there are multiple
reports > grade 2 for one eye, each report
should be counted in this category.
11 Total # of Eyes This number includes the number of eyes
Reporting Staining: that had staining reports one or more times
during the study. Even if there are multiple
reports for one eye, only one report should
be counted.
12-14 Edema Categories The instructions for completing the edema
entries correspond exactly to the
instructions for completing the staining
categories (Items 8-10 above). Follow the
instructions for Items 8-10 substituting the
word "edema" for the word "staining."
15-17 Injection Categories The instructions for completing the injection
entries correspond exactly to the
instructions for completing the staining
categories (Items 8-10 above). Follow the
instructions for Items 8-10 substituting the
word "injection" for the word "staining."
18-20 Neovasc. Categories The instructions for completing the
neovascularization entries correspond exactly
to the instructions for completing the
staining categories (Items 8-10 above).
Follow the instructions for Items 8-10
substituting "neovascularization" for the
word "staining."
21 Total Visits This includes the total number of visits
occurring during this time interval.
22 Total Missed Visits This includes the total number of missed
visits during this time interval.

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CLIN--APPENDIX E
“MODIFIED” TREND ANALYSIS PROFILE (TAP)
SPONSOR/510(K) No. TRADE NAME:
No. Eyes Enrolled: Generic Indication
VISIT NUMBER
1 2 3 4 5 6 TOTALS
TIME IN STUDY
TOTAL # OF EYES
D/C EYES
AVERAGE WEAR TIME
LENS REPLACEMENTS
ALL ADVERSE REACTIONS
ALL CORNEAL ULCERS
ALL IRITIS
TOTAL REPORTS STAINING
STAINING REPORTS > GR 2
TOTAL NUMBER OF EYES REPORTING STAINING
TOTAL REPORTS EDEMA
EDEMA REPORTS > GR 2
TOTAL NUMBER OF EYES REPORTING EDEMA
TOTAL REPORTS INJECTION
INJECTION REPORTS > GR 2
TOTAL NUMBER OF EYES REPORTING INJECTION
TOTAL REPORTS NEOVASC.
NEOVASC. REPORTS > GR 2
TOTAL NUMBER OF EYES REPORTING NEOVASCULARIZATION
TOTAL VISITS
TOTAL MISSED VISITS

` 160
SHELF-LIFE PROTOCOL
Listed below is guidance for establishing, or extension of, shelf-life
(expiration date) for sterile contact lens care solutions and tablets:
A. Manufacturing/Chemistry:
The manufacturer should demonstrate the stability of the solution or
tablet over time as packaged and stored under the proposed storage
conditions. Manufacturers should provide their shelf-life protocol and
have shelf-life data sufficient to support their labeled expiration date
prior to marketing their product.
The aging of the solution in the storage containers should be initiated
as soon as possible. The stability tests should include all parameters
(if applicable) such as pH, tonicity, viscosity, surface tension, active
ingredients, and physical appearance. Accelerated aging up to 45oC may
be used as supporting evidence of stability. Generally every 10oC
increase for tested temperature will enhance the expiration date by a
factor of two compared to the normal storage temperature. Containers
selected randomly from a minimum of 3 lots are required for shelf-life
tests for the smallest container size. Lot number, manufacturing date,
testing date, and analytical methodology for the active ingredients
should be provided. Note: Manufacturers may release product with
shelf-life based initially on accelerated stability data. However, the
shelf-life protocol should provide for ongoing "real-time" stability
data to support the accelerated data.
The size of the container tested should be the same as that intended to
be marketed. Generally, if the solution is susceptible to chemical
degradation via light and oxygen, the greater the internal contact of
the solution with the container surface the greater the chance of
chemical degradation. The degradation, therefore, is more likely to
occur in smaller containers because the ratio of solution volume to
internal surface area decreases as the container size decreases. For
this reason, DOD may grant 510(k) clearance of a solution in a container
larger than that used for stability testing, but usually not a container
smaller than tested unless additional testing is conducted by the
sponsor according to cleared/approved protocol and product
specifications remain unchanged. This policy may extend to containers
eight times the size tested provided the containers are constructed of
the same materials. Currently, the largest size container marketed is a
16 fl. oz. container.
B. Microbiology:
Manufacturers should demonstrate the preservative effectiveness or
bacteriostasis and sterility for multi-dose packaged solutions to
establish shelf-life. An approved extension of shelf-life protocol
permits the manufacturer to extend shelf-life up to the time designated
in the protocol without submitting a new 510(k). Preservative
effectiveness (Micro--Appendix A) and bacteriostasis testing (Micro-
Appendix C) are conducted, as applicable.
Maintenance of sterility over a product's shelf-life may be determined
by USP sterility testing or by validated package integrity testing. If
sterility testing is performed, product samples should be stored at

` 161
temperatures up to 37oC. These random samples should be from 3 lots of
approximately the same age. The samples should be stored in a manner
that maximally tests the container/closure system (e.g., inverted).
Shelf-life can be established using "real time" data from sterility and
preservative effectiveness or bacteriostasis testing. Shelf-life based
on "real time" data may be given a shelf-life equal to the time which
packaged solutions are stored at ambient temperature (generally 23+2oC).
For example, samples stored at ambient temperature (generally 23+2oC)
for 24 months may be granted a 24-month (2-year) expiration date if they
have passed the microbiology stability testing and physical/chemical
stability requirements outlined in the extension of shelf-life protocol.
Accelerated studies may be run for preservative effectiveness testing,
bacteriostasis testing and validated package integrity testing at a
maximum temperature of 45oC to establish shelf-life. Manufacturers
should support the accelerated data with ongoing "real-time" data.
Accelerated shelf-life estimates should be calculated using the
following information:
1. Accelerated Storage Time refers to the actual storage time at
elevated temperature for packaged solutions.
2. Acceleration Factor refers to the factor used to extrapolate the
aging of the samples at the elevated temperature. The
Acceleration Factor should be based on Q10 equal to 2.0 for each
10oC above ambient temperature.
Accelerated shelf-life estimates may be calculated as follows for
samples stored only at the accelerated temperature:
Step 1. Calculate the Acceleration Factor based on the temperature
difference between the elevated temperature and the ambient
temperature. For example, based on a 15oC rise above
ambient temperature, the Acceleration Factor may be
calculated as 2.0(1.5) = 2.83; the Acceleration Factor based
on a 20oC rise above ambient temperature is 2.0(2) = 4.0.
Step 2. Accelerated Storage Time x Acceleration Factor
= Accelerated Age or Shelf-life
For samples which are stored at ambient temperature prior to being
stored at the elevated temperature, the age of the sample at the start
of the accelerated study can be added to the Accelerated Age when
calculating shelf-life.
A product may be marketed in a container up to 8 times larger than the
container tested for shelf-life (identical container and closure
system). Currently, the largest size container marketed is a 16 fl. oz.
container. If a product is to be marketed in a container smaller than
the container previously tested for shelf-life, the manufacturer should
perform the applicable shelf-life testing.
Ordinarily, FDA will not require a 510(k) for extension of shelf-life
beyond the shelf-life requested in the original 510(k) provided the same
protocol is followed.

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FDA will consider alternative methods to sterility testing to support
package integrity provided a method is adequately validated.
For multi-dose preserved contact lens care products, the labeling and
instructions for use may include a statement recommending the period for
which a product should be used after opening (discard date). This
recommended period should be based on container size, projected number
of uses, and frequency of use, as determined by the manufacturer. For
bacteriostatic solutions, a discard date should be determined according
to the bacteriostasis test (Micro--Appendix C).

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QUESTIONS AND ANSWERS
Q1: Because this guidance document is the "special control" which is the basis
for reclassification, am I required to conduct every test listed for a
given product?
A1: The term "special control" refers to a variety of items such as guidance
documents or product specific labeling which are available to provide
reasonable assurance of safety and effectiveness within the scope of
Class II regulation of a medical device. As stated in the Introduction
Section, Purpose of Document, this guidance provides comprehensive
directions to manufacturers for collecting and preparing data for a
510(k). The preclinical and clinical testing is that which FDA believes
to be acceptable to establish substantial equivalence. Persons may choose
to follow the guidance, or may follow different data collection and
preparation procedures. Alternative procedures will need to be justified
to CDRH's satisfaction that they are applicable to demonstrate substantial
equivalence. The specific scientific items listed in the guidance
represent the minimum which should be addressed to demonstrate substantial
equivalence. In some cases it may be possible to address the item without
conducting or repeating the specific test.
Q2: What is the difference between intended use and indication for use?
A2: The intended use of a medical device is defined in 21 CFR 801.4 and
guidance is provided in CDRH Blue Book Memorandum K86-3. It refers to how
a product is to be used. The GUIDANCE FOR INDUSTRY--PREMARKET
NOTIFICATION (510(k)) GUIDANCE DOCUMENT FOR CONTACT LENS CARE PRODUCTS
includes a variety of product specific intended uses as exist in 1996 with
current technology. An example of a product specific intended use is an
in-eye lubricating drop. The indication for use is a specific statement
which includes the intended use of the device. An indication for the in-
eye drop may be limited to either hydrophobic (RGP) or hydrophilic (soft)
lenses, or it may include both. If a product had been legally marketed
for use with soft lenses only, and later a manufacturer wants to market it
for both soft and RGP lenses, this would be a change in indication, but
not a change in the intended use since the product specific use remains
the same. A new 510(k) application is required for either a change in
intended use or a change in indication.
Q3: How do I use a product specific matrix for a "me-too" product, and for a
product which isn't "me-too"?
A3: The matrices are designed to provide guidance for products with the same
active ingredients as the predicate device (so called "me-too products"),
as well as products which contain different active ingredients, for the
various product specific intended uses. When developing a product with
the same active ingredient, a manufacturer determines the concentration of
the active ingredient in the formulation then refers to the appropriate
column for guidance. Recommended testing may vary depending on whether
the active ingredient is formulated at a higher, lower, or the same
concentration as the predicate device. When a manufacturer develops a

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formulation which contains a different active ingredient from the chosen
predicate device, or when the active ingredients are new for ophthalmic
use, the fourth column is provided for guidance.
Q4: Why is a "new ingredient for ophthalmic use" grouped in the same matrix
column as a "different active ingredient" for a given product specific
intended use"?
A4: As stated in Section II., General Manufacturing Information, the guidance
focuses primarily on active ingredients. The active ingredient a
manufacturer chooses to use to achieve the product specific intended use,
(e.g. cleaner, disinfecting product, etc.) will often be the same active
ingredient as found in the predicate device. Additional testing is
recommended when the manufacturer uses a different active ingredient than
found in the predicate device since that case generally represents the
need for additional information to determine substantial equivalence.
Q5: What are the different hydrophilic and rigid gas permeable (RGP) lens
groups and why are tests conducted with representative groups?
A5: The lens groups are described in detail in the PREMARKET NOTIFICATION
(510(k)) GUIDANCE DOCUMENT FOR DAILY WEAR CONTACT LENSES. There are four
hydrophilic groups based on ionic surface charge and water content (Groups
I, II, III, and IV). There are also four RGP groups based on material
composition. However, the majority of currently marketed RGP lenses fall
into only two of the four groups; silicone acrylate and fluorosilicone
acrylate. The pure fluoropolymer group consists of only one polymer which
currently is not marketed, and the last group represents an assortment of
RGP materials which are generally no longer marketed or rarely
encountered. It is primarily the solution manufacturer’s responsibility,
not the lens manufacturer’s, to demonstrate compatibility with the
indicated lens material groups.
Q6: If my product is already approved for use with a soft lens, do I have to
do any testing to change the indication to include use with RGP lenses, or
may I just revise the labeling as necessary? What about the reverse
situation (i.e. going from RGP to soft lens use)?
A6: In either case, a new 510(k) will be necessary, although the content may
differ. Soft lens use may be a worst case in some situations, so the
recommended tests in the product specific matrix need to be considered and
addressed individually. A solution for RGP lenses may prove to be
incompatible with soft lenses due to lens absorption or adsorption of an
ingredient. Because the manufacturer should know the product very well,
characteristics of the active and inactive ingredients will dictate
whether toxicology screening needs to be repeated, or if preservative
uptake studies are necessary. The guidance is designed to rely on
preclinical testing to answer the major part of the compatibility
question. The characteristics of the product, along with the indication
change, will dictate how much or how little testing is necessary and which
areas may be addressed by explanation.
Q7: Why are contact lens solutions intended for chemical disinfection of
lenses not generally labeled as "chemical disinfectants"?

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A7. The distinction is made to differentiate contact lens disinfecting
solutions from more potent chemical disinfectants used to prevent patient
to patient transmission of microorganisms both on medical devices which
are disinfected between patients, and on inanimate surfaces. The term
"chemical disinfectant" generally applies to germicidal products
demonstrating a six log reduction in microorganisms using Association of
Official Analytical Chemists (AOAC) test methods. Historically contact
lens solutions intended to destroy ocular pathogens have been labeled as
disinfecting solutions, even though many products do not meet the same
efficacy criteria as other chemical germicides. The lower recommended
efficacy criteria outlined in this guidance document for contact lens
disinfecting solutions are intended to minimize the risks of toxicity to
ocular tissue from the contact lens care solutions while providing a
regimen for effective reprocessing of contact lenses.
Q8: What is the difference between a "chemical disinfecting solution" and a
"chemical disinfection system"?
A8: As defined in Micro--Appendix B, Disinfection Efficacy Testing, there are
two levels of antimicrobial efficacy with performance criteria modeled
after the ISO/CEN draft requirements. For both levels, cleaning is an
integral part of the lens care process necessary to achieve proper lens
care. A product may be labeled as "disinfecting solution" only when it
meets the higher level of antimicrobial efficacy for the "Stand-Alone"
test. The "Regimen" procedure evaluates the adequacy of the entire
"chemical disinfection system for solutions which fail to meet the Stand-
Alone efficacy criteria."
Q9: If I want to change my bottle size or the material the bottle is made
from, do I need to submit a new 510(k)?
A9: In Section IV. Modifications of Approved Contact Lens Care Products
requiring a 510(k), this question is addressed under Section B., examples
which should not require a 510(k). As stated in the Shelf-Life Protocol
Appendix, there can be greater chemical degradation in susceptible
solutions when the container size is decreased since the ratio of solution
volume to internal surface is decreased. For that reason, stability test
data are necessary to establish a shelf-life for the smallest container.
A new 510(k) should not be necessary provided the testing performed
demonstrates that the product specifications remain unchanged and proper
documentation is included in the device master record. Likewise, a change
in packaging material should not be necessary provided the conditions
noted in Section IV.B.4. are met. This packaging change guidance is a
continuation of a policy in place while these products were regulated
under Class III. At that time packaging changes meeting specified
criteria were reportable in the Annual Report to the PMA rather than under
a PMA supplement.
Q10: The Toxicology Appendix lists three minimum recommended toxicology tests
under Section II., but the Acute Oral Toxicity is not recommended in all
cases in the product specific matrices. What is really necessary?
A10: This is generally addressed as a labeling precaution when appropriate. If
a predicate device with the same active ingredient is used, the predicate
device labeling would already address this item. If a new active

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ingredient is used, information on oral toxicity may already be available,
so the test may not have to be actually conducted to address this item.
Q11: The statement "when clinical performance data are necessary" is somehow
tied into the "physical/chemical, microbiological and toxicological data
to support a claim." What does this really mean?
A11: The guidance really emphasizes preclinical testing. In many cases, a
side-by-side analysis with the predicate device will go a long way to
demonstrating substantial equivalence. The tests and parameters noted in
Section II. General Manufacturing Information introductory paragraph and
Section A, and in Section IV. Modifications of Approved Products A.1 list
the primary physical/chemical preclinical comparisons. When these test
data demonstrate a difference from the predicate device, additional
clinical performance data are recommended.
Q12: With so many options for controls in clinical design, how do I decide
which one to choose?
A12: In general, the complexity of the study design will reflect the uniqueness
of the product. For example, a clinical study of a “me-too” product with
the same active ingredients may be addressed without a concurrent control.
If the product has different active ingredients from the predicate
device, but does not contain a new ingredient for ophthalmic use, then a
control group would be appropriate. When the new ingredient is also a new
ingredient for ophthalmic use, randomization may be appropriate.
Q13: Do I need 510(k) clearance for separate instructions to practitioners for
in-office disinfection?
A13: Yes. The additional 510(k) clearance pertains to specific instructions
the manufacturer may want to develop for in-office disinfection of trial
lenses. Refer to Section III. C. Chemical Disinfecting Products for
current labeling and test recommendations intended to address the
additional safety considerations associated with trial lens disinfection
between patients.
Q14: Can I add catchy statements to my product's labeling to give it a
marketing edge?
A14: When developing product labeling, the manufacturer should refer to the
predicate device labeling for the product specific intended use and
directions for use. The manufacturer has the responsibility for
familiarity with applicable regulations to avoid misbranding his or her
device. A determination of substantial equivalency will be based on the
predicate device's labeling, as well as the product specific intended use
and directions for use. FDA primarily reviews medical device claims which
concern the safety and/or effectiveness of the device as well as those
which address inherent properties of the device. Manufacturers should be
aware that additional product attribute labeling claims such as
comparative claims to another manufacturer’s product will usually require
significant data above the minimum necessary information recommended in
the GUIDANCE FOR INDUSTRY--PREMARKET NOTIFICATION (510(k)) GUIDANCE
DOCUMENT FOR CONTACT LENS CARE PRODUCTS to determine substantial
equivalency.

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Q15: Why do I have to use all those boxes in my labeling from that Write-it-
Right example? There's no regulation that says I have to do it that way.
A15: Yes, you are correct. There are no specific regulations concerning this
model. The Write-it-Right example is included for the benefit of those
manufacturers who wish to utilize that labeling model. The Write-it-Right
booklet referenced is available from CDRH/DSMA. If a manufacturer uses
that model, it is recommended that the concepts be followed, or a
justification and explanation be provided for deviations from the model.
For example, Write-it Right suggests that the labeling be geared to a
seventh grade reading level. If a different reading level is used, an
explanation should be provided.
Q16: Why do I need to submit a new 510(k) if I want to have my saline solution
used as a rewetting agent? Do I really need a clinical study for
something like that?
A16: These two questions involve more than one answer. If the saline product
is already cleared for marketing, then it certainly would be possible to
address the clinical study issue. Remember back to the first question?
Not every test needs to be conducted if it can be adequately addressed.
It's very difficult to write a guidance to clearly direct a manufacturer
to each possible situation. The matrices are mainly constructed to
provide guidance for a new manufacturer of a new product. In that
situation, there's nothing to establish the biocompatibility of a product,
even if it's a "me-too" product. That's why the toxicology screening
tests are listed in the matrix. Because manufacturing processes and
inactive ingredients may vary, there need to be some data to support
biocompatibility, either toxicology and/or clinical data. The matrices
are also to be used for guidance when legally marketed products are
modified. In that situation, some of the test data already available may
be applicable to address a specific item.
As for the need for a new 510(k), the change in labeling is a new
indication for use of the saline and requires a 510(k). In addition,
both Sections III. D. Multi-purpose Solution and E. In-eye Contact Lens
Solutions address issues related to current policy for in-eye products.
In order to both reduce the risk of contamination during use and to
facilitate ease of use, lubricating and rewetting solutions should be
packaged in bottle sizes not to exceed 30 ml. FDA believes that limiting
the indications for in-eye use solutions to a single intended use (even
when the chemical composition is identical to a multi-purpose solution,
saline or conditioning solution) enhances product safety and encourages
consumer compliance with safe lens care practices.
End of Guidance