Certain Ophthalmic
Products: Policy
Regarding Compliance
With 21 CFR Part 4
Guidance for Industry
This guidance is for immediate implementation.
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR
10.115(g)(2). Submit one set of either electronic or written comments on this guidance at any
time. Submit electronic comments to https://www.regulations.gov. Submit written comments to
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852. You should identify all comments with the docket number
listed in the notice of availability that publishes in the Federal Register.
For questions regarding this document, contact the office of Combination Products at 301-796-
8930 or combination@fda.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Office of Combination Products (OCP)
March 2022
Combination Products
Certain Ophthalmic Products:
Policy Regarding Compliance
With 21 CFR Part 4
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
and/or
Office of Policy
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 66, Room 5431
Silver Spring, MD 20993-0002
Email: CDRH-Guidance@fda.hhs.gov
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Office of Combination Products (OCP)
March 2022
Combination Products
Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 2
III. DISCUSSION .................................................................................................................... 2
A. Products Subject to an Approved Application and Products Marketed Under Section 505G
of the FD&C Act ............................................................................................................................ 3
B. Products Subject to a Pending Application ................................................................................. 4
Contains Nonbinding Recommendations
Certain Ophthalmic Products: Policy Regarding
Compliance With 21 CFR Part 4
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. INTRODUCTION
This guidance is intended to provide information to applicants and manufacturers regarding
compliance with the requirements in part 4 (21 CFR part 4) for ophthalmic drugs 1 packaged with
eye cups, eye droppers, or other dispensers. This guidance applies to products with pending
applications, 2 approved products, and products marketed pursuant to section 505G of the Federal
Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355h) without an approved application
under section 505 of the FD&C Act (21 U.S.C. 355) (commonly referred to as over-the-counter
(OTC) monograph drugs).
FDA is implementing this guidance without prior public comment because the Agency has
determined that prior public participation is not feasible or appropriate (21 U.S.C.
371(h)(1)(C)(i) and 21 CFR 10.115(g)(2)). We made this determination because FDA needs to
communicate its compliance policy in a timely manner given the urgency of these issues
following the decision of the U.S. Court of Appeals for the District of Columbia Circuit in Genus
Medical Technologies LLC v. U.S. Food and Drug Administration. Although this guidance is
immediately in effect, FDA will consider all comments received and determine whether
revisions to the guidance document are appropriate (§ 10.115(g)(3)).
The contents of this document do not have the force and effect of law and are not meant to bind
the public in any way, unless specifically incorporated into a contract. This document is intended
only to provide clarity to the public regarding existing requirements under the law. FDA
guidance documents, including this guidance, should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use of the word should in Agency
guidance means that something is suggested or recommended, but not required.
1
The term drug as used in this guidance refers to both human drugs and biological products unless otherwise
specified.
2
For the purposes of this guidance, pending applications include applications on which FDA has taken an action that
is not an approval action and that are not currently pending review before the Agency (i.e., applications that have
been tentatively approved or applications that have received a complete response letter) and applications currently
pending review before the Agency (including supplements to approved applications).
1
Contains Nonbinding Recommendations
II. BACKGROUND
In accordance with § 200.50(c) (21 CFR 200.50(c)), eye cups, eye droppers, and other dispensers
intended for ophthalmic use (collectively referred to as ophthalmic dispensers) have been
regulated as drugs when packaged together with the ophthalmic drug with which they were
intended to be used. Regulating ophthalmic dispensers as drugs is a departure from how FDA
regulates other devices that are packaged with the drugs with which they are intended to be used.
Specifically, when a device is packaged together with the drug with which it is intended to be
used, FDA regulates that drug and the device together as a combination product (see § 3.2(e) (21
CFR 3.2(e)).
On April 16, 2021, the U.S. Court of Appeals for the District of Columbia Circuit issued its
decision in Genus Medical Technologies LLC v. U.S. Food and Drug Administration, 994 F.3d
631 (D.C. Cir. 2021). The Genus court stated “[e]xcepting combination products, . . . devices
must be regulated as devices and drugs — if they do not also satisfy the device definition —
must be regulated as drugs.” 3 In implementing this decision, FDA has determined that the
language in § 200.50(c) indicating that ophthalmic dispensers are regulated as drugs when
packaged with ophthalmic drugs is now obsolete, because these articles meet the device
definition. Therefore, FDA intends to regulate these products as drug-led combination products
composed of a drug constituent part that provides the primary mode of action and a device
constituent part (an ophthalmic dispenser). Because the drug constituent part provides the
primary mode of action, generally the Center for Drug Evaluation and Research (CDER) will
have primary jurisdiction over these products. 4
III. DISCUSSION
Before the Genus decision, ophthalmic dispensers packaged together with the ophthalmic drug
with which they were intended to be used were regulated as drugs. Therefore, products
consisting of an ophthalmic drug packaged with an ophthalmic dispenser were not regulated as
combination products as defined in § 3.2(e) and were not subject to the requirements in part 4.
However, following the Genus decision, an ophthalmic dispenser that meets the definition of
device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)) and that is packaged together with
an ophthalmic drug is now regulated as a device constituent part (see § 3.2(e)). This change
impacts products subject to pending applications, approved products, and OTC monograph
drugs.
3
For more information on FDA’s implementation of the Genus decision, see “Genus Medical Technologies LLC
Versus Food and Drug Administration; Request for Information and Comments,” 86 FR 43553 (Aug. 9, 2021).
4
Some of these combination products may consist of an ophthalmic dispenser packaged with a biological product
that would be assigned to the Center for Biologics Evaluation and Research (CBER) if marketed on its own. In
these instances, CBER will have primary jurisdiction over the combination product.
2
Contains Nonbinding Recommendations
A. Products Subject to an Approved Application and Products Marketed Under
Section 505G of the FD&C Act
We recognize that some applicants and manufacturers may need to develop policies and
procedures necessary to comply with the requirements in part 4. Therefore, for a period of 12
months following the publication of this guidance, FDA generally does not intend to take action
with respect to noncompliance with part 820 (21 CFR part 820) as described in part 4, subpart A,
with respect to ophthalmic products that were not previously regulated as combination products
because of the now obsolete language in § 200.50(c). We believe that this 12-month period
provides these applicants and manufacturers sufficient time to develop and implement the
policies and procedures necessary to comply with these newly applicable requirements.
As described in the FDA guidance for industry and FDA staff Current Good Manufacturing
Practice Requirements for Combination Products (January 2017), 5 although pharmaceutical
development focuses on drug considerations, many pharmaceutical development practices (for
example, Quality-by-Design principles), 6 if broadened to take into account the other constituent
parts of combination products and how they interrelate, can be leveraged and built upon when
demonstrating compliance with part 4 requirements for a combination product. For example, it
would be appropriate to leverage existing data in developing a design history file if a
combination product is subject to design control requirements but has not been developed under
design controls. Existing specifications may become part of the required design output
documentation. Similarly, testing performed before distribution of the combination product may
be included as documentation of design verification and validation.
The applicant or manufacturer of the combination product is responsible for assembling available
information and assessing what, if any, additional information and evidence may be needed
(such as additional testing or documentation of the design control activities) to address all
aspects of design control that are needed to support the manufacture of the product as currently
marketed, ensure its safety and effectiveness, and support any future changes to that
product. 7 Applicants and manufacturers are not expected to retroactively prepare certain parts of
the development plan or conduct design review meetings for the product as currently marketed
because the development stages that these activities would support have already
occurred. However, they should put a design and development plan in place, and they should
have procedures for design review meetings in place to support future design activities such as
future design changes.
Additionally, some ophthalmic products that were not previously regulated as combination
products because of the now obsolete language in § 200.50 incorporate lower-risk device
constituent parts, for example, eye dropper bottles/ampules that administer the drug directly to
the eye. The Agency is evaluating the application of part 820 quality system (QS) requirements
to combination products that include such constituent parts. Until FDA has further considered
the application of these requirements to these combination products, the Agency generally does
5
We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
6
See FDA guidance for industry Q8(R2) Pharmaceutical Development (November 2009).
7
§ 820.30.
3
Contains Nonbinding Recommendations
not intend to take action with respect to noncompliance with any applicable part 820
requirements for these ophthalmic products. When the Agency publishes its current thinking on
application of part 820 requirements to these combination products, FDA will also address its
timing expectations for applicants and manufacturers of such combination products to come into
compliance with any applicable part 820 requirements. If you have questions regarding whether
your combination product includes such a device constituent part, we recommend that you
contact CDER’s Office of New Drugs or Office of Generic Drugs, as appropriate.
However, if you submit a supplement to an approved application for an ophthalmic product that
was previously not regulated as a combination product due to the now obsolete language in §
200.50, the information in subsection III.B below may apply to the supplement if the supplement
includes a change related to product quality or to the device facility information (e.g., a finished
product manufacturing site change, a chemistry, manufacturing, and controls-related change, or a
new device constituent part).
In addition, for a period of 12 months following the publication of this guidance, FDA does not
intend to take action with respect to the requirements set forth in part 4, subpart B
(postmarketing safety reporting requirements for combination products), against any applicant
(as defined in 21 CFR 4.101) of an ophthalmic product that was not previously regulated as a
combination product because of the now obsolete language in § 200.50. 8
B. Products Subject to a Pending Application
Generally, FDA intends to request that you provide an updated Form FDA 356h to your pending
application, indicating that the product is a combination product and identifying all facilities
involved in the manufacturing of the combination product, including all facilities involved in the
manufacturing of each constituent part and all facilities responsible for the disposition (e.g.,
release) of the combination product. 9 Any additional impact on products subject to pending
applications currently under review would depend on the risk profile of the product, the type of
application, and the information that was already provided in your application. The following
circumstances may arise during the review of your pending application:
FDA may determine that, based on the risk profile of your combination product, information to
demonstrate compliance with any applicable device QS regulation requirements is most
appropriately assessed during inspection following approval; in such cases, this information
should not be submitted in the application but must be available upon inspection to demonstrate
your compliance with part 4. 10
8
Information on postmarketing safety reporting requirements for combination products is available at
https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reporting-
combination-products.
9
FDA also recommends that applicants review other guidances for industry that apply to CDER-led drug-device
combination products to determine if any additional information should be submitted in the application.
10
21 CFR part 4. See section III.A for a description of any enforcement discretion that may be applicable to
inspections that take place after approval.
4
Contains Nonbinding Recommendations
In other situations, FDA may determine that, based on the risk profile of your combination
product, information to demonstrate compliance with the device QS regulation should be
submitted for review as part of the quality assessment of your application. If you are using a
drug current good manufacturing practice-based operating system, in addition to demonstrating
compliance with 21 CFR parts 210 and 211, you also should submit summary information to
describe how your firm has applied each applicable provision in the device QS regulation
described in § 4.4(b), including descriptions of the specific procedures and activities conducted
by your firm and references to the types of protocols used by your firm for each activity. If you
have not submitted this information, you may be asked to submit additional information in
response to an information request. 11
Also, FDA may determine that a pre-approval inspection of the facility performing combination
product manufacturing is warranted before your pending application can be approved. However,
given what has been known generally about the products subject to this guidance, for pending
submissions of a product subject to this guidance, FDA anticipates that pre-approval assessment
of your compliance with any applicable QS regulation requirements generally will not need to
include facility inspection against these requirements. Rather, FDA anticipates that assessment
of information demonstrating compliance with such requirements generally will be covered as
described above.
FDA’s review of a pending application for a combination product generally does not include a
review of the applicant’s ability to comply with the postmarketing safety reporting requirements
in part 4, subpart B. However, applicants must comply with these requirements if their
application is approved. We recognize that some applicants may need additional time to develop
and implement policies and procedures to comply with these part 4 requirements. Thus, for
approved products subject to these requirements, FDA generally does not intend to take action
with respect to noncompliance with these part 4 requirements for a period of 12 months after
publication of this guidance.
11
See discussion of design control in section III.A.
