Manufacturing Site Change Supplements: Content and Submission: Guidance for Industry and Food and Drug Administration Staff

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

On February 2, 2024, FDA published the final rule to amend the Quality System (QS) regulation
in 21 CFR part 820 (89 FR 7496, effective February 2, 2026). The revised 21 CFR part 820 is
now titled the Quality Management System Regulation (QMSR). The QMSR harmonizes quality
management system requirements by incorporating by reference the international standard
specific for medical device quality management systems set by the International Organization for
Standardization (ISO), ISO 13485:2016. The FDA has determined that the requirements in ISO
13485 are, when taken in totality, substantially similar to the requirements of the QS regulation,
providing a similar level of assurance in a firm’s quality management system and ability to
consistently manufacture devices that are safe and effective and otherwise in compliance with the
Federal Food, Drug, and Cosmetic Act (FD&C Act).
This guidance document was issued prior to the effective date of the final rule. FDA encourages
manufacturers to review the current QMSR to ensure compliance with the relevant regulatory
requirements.
On November 26, 2024, FDA issued a guidance titled “Transitional Enforcement Policy for
Ethylene Oxide Sterilization Facility Changes for Class III Devices.” This Ethylene Oxide
Sterilization guidance provides information regarding FDA recommendations and general
principles PMA and HDE holders of Class III devices sterilized by ethylene oxide (EtO) whose
products are affected by the potential, actual, or temporary operation reductions at a sterilization
facility may reference if they wish to have FDA consider whether the exercise of enforcement
discretion relating to the implementation of certain types of sterilization site changes is
appropriate.
On November 2, 2023, FDA issued a guidance titled “Enforcement Policy for Certain
Supplements for Approved Premarket Approval (PMA) or Humanitarian Device Exemption
(HDE) Submissions.” This guidance provides clarification on FDA’s policies and regulatory
review expectations for certain limited modifications affecting the safety and effectiveness of a
device required to have an approved PMA or the safety and probable benefit of a device required
to have an approved HDE at the conclusion of the COVID-19 public health emergency.

Contains Nonbinding Recommendations
Manufacturing Site Change
Supplements: Content and
Submission
Guidance for Industry and Food and
Drug Administration Staff
Document issued on December 17, 2018.
The draft of this document was issued on October 21, 2015.
For questions about this document regarding CDRH-regulated devices, contact the Premarket
Approval Staff at 301-796-5640.
For questions about this document regarding CBER-regulated devices, contact the Office of
Communication, Outreach and Development (OCOD) by calling 1-800-835-4709 or 240-402-
8010.
U.S. Department of Health and Human
Services
Food and Drug Administration
Center for Devices and Radiological Health
Center for Biologics Evaluation and Research

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Preface
Public Comment
You may submit electronic comments and suggestions at any time for Agency consideration to
https://www.regulations.gov. Submit written comments to the Dockets Management Staff,
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD
20852. Identify all comments with the docket number FDA-2015-N-3454. Comments may
not be acted upon by the Agency until the document is next revised or updated.
Additional Copies
CDRH
Additional copies are available from the Internet. You may also send an e-mail request to
CDRH-Guidance@fda.hhs.gov to receive an electronic copy of the guidance. Please use the
document number 1269 to identify the guidance you are requesting.
CBER
Additional copies are available from the Center for Biologics Evaluation and Research
(CBER) by written request, Office of Communication, Outreach and Development (OCOD)
(HFM-40), 10903 New Hampshire Ave., Bldg. 71, rm. 3128, Silver Spring, MD 20993-0002,
or by calling 1-800-835-4709 or 240-402-8010, or by e-mail at ocod@fda.hhs.gov or from
the Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/default.htm.

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Table of Contents
I. INTRODUCTION............................................................................................................................................1
II. BACKGROUND ..............................................................................................................................................1
III. SCOPE OF GUIDANCE ...............................................................................................................................3
A. 	DEFINITIONS………………………………………………………………………………………..…3
IV. SUBMISSIONS FOR MANUFACTURING SITE CHANGES .................................................................6
A. 	W HAT IS A MANUFACTURING SITE CHANGE AND WHEN SHOULD IT BE SUBMITTED AS A SITE CHANGE
SUPPLEMENT VERSUS A 30-D AY N OTICE ? ...............................................................................................6
B. 	W HAT SHOULD BE SUBMITTED IN THE SITE CHANGE SUPPLEMENT?....................................................... 11
C. 	D ETERMINING WHETHER AN INSPECTION MAY BE NEEDED. ................................................................... 14
D. 	ADDITIONAL RESOURCES ...................................................................................................................... 15

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Manufacturing Site Change Supplements:
Content and Submission
Guidance for Industry and
Food and Drug Administration Staff
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 staff
or Office responsible for this guidance as listed on the title page.
I. Introduction
This guidance explains FDA’s current thinking regarding the following:
(A) 	What constitutes a manufacturing site change and when you should submit a PMA
supplement for a site change;
(B) 	What documentation you should submit in a site change supplement; and
(C) 	The general factors FDA intends to consider when determining whether to conduct an
establishment inspection prior to approval of a site change supplement.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and 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.
II. Background
Under section 515(d)(5) of the Federal Food, Drug, and Cosmetic (FD&C) Act, 21 U.S.C. §
360e(d)(5), a supplemental application to an approved PMA (PMA supplement) must be
submitted for review and approval by FDA before making a change that affects the device’s
safety or effectiveness, unless such change is a modification in a manufacturing procedure or
method of manufacture, which would be eligible for a 30-day notice. The PMA regulations
provide general criteria in 21 CFR 814.39 for determining when PMA holders (hereinafter
referred to as “applicants”) are required to submit a PMA supplement or are eligible to submit a

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30-day notice. Under 21 CFR 814.39(a)(3), a PMA holder must submit a PMA supplement
when it “use[s] a different facility or establishment to manufacture, process, or package the
device,” and the change affects the device’s safety or effectiveness.
With respect to establishment inspections, section 510(h) of the FD&C Act (21 U.S.C. § 360(h))
requires every registered establishment to be subject to inspections pursuant to section 704 of the
FD&C Act (21 U.S.C. § 374) and every such establishment engaged in the manufacture,
propagation, compounding, or processing of a device or devices will be inspected in accordance
with a risk-based schedule.
In March 1996, CDRH sent a letter to the medical device industry that announced a one-year
pilot to improve the processing of PMA supplements for changes in manufacturing sites. The
letter discussed the need to improve the speed and efficiency of CDRH review and approval of
manufacturing site change supplements, and stated that CDRH did not require a preapproval
inspection for all manufacturing site changes. That letter described conditions under which a site
generally would or would not be inspected. CDRH later developed the draft guidance entitled,
“Likelihood of Facilities Inspections When Modifying Devices Subject to Premarket Approval,”
which was issued on August 5, 1999. This guidance was not finalized.
The PMA supplements described in the March 1996 letter and the 1999 draft guidance were
called “site change supplements” or, if no preapproval inspection was required, they were termed
“express supplements.” FDA now identifies all such submissions as “site change supplements”
with a designation of whether or not an inspection is needed before the change can be
implemented. Based on feedback from industry and the Agency’s experience over many years,
FDA has made substantial revisions and updates to the 1999 draft guidance, which is being
replaced by this guidance, “Manufacturing Site Change Supplements: Content and Submission.”
This guidance is intended to help industry decide when a change in manufacturing site should be
submitted in a PMA site change supplement. The guidance is also intended to help industry
anticipate when a preapproval inspection in connection with a PMA supplement for a
manufacturing site change will likely be needed to evaluate the firm’s implementation of the
Quality System (QS) regulation requirements, 21 CFR Part 820. As a result, this guidance
should help firms manage the timeframes associated with implementing the changes in the
manufacturing site and any processes, methods, procedures, qualifications, and validations.
Regardless of whether or not an FDA preapproval inspection will be conducted, or whether a
PMA supplement should be submitted, manufacturers of class III finished devices must comply
with the QS regulation requirements applicable to its operations, which are found in 21 CFR Part
820. By developing and implementing QS processes, manufacturing-related problems can be
minimized when using a different facility or establishment to manufacture, process, or package a
device.
FDA also has issued other general guidances regarding PMA supplements and 30-day notices.
In the guidance, Modifications to Devices Subject to Premarket Approval (PMA) - The PMA
Supplement Decision-Making Process – Guidance for Industry and FDA Staff1 , FDA discusses,
1 For further information on PMA supplement decision-making process, please refer to this guidance, available at
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM089360.
pdf.

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in Section G, “When to Submit a Manufacturing Site Change Supplement,” that it plans to issue
a separate guidance on manufacturing site change supplements and when an inspection is likely
to occur. This “Manufacturing Site Change Supplements: Content and Submission” guidance is
that separate guidance.
FDA issued the guidance, “30-Day Notices, 135-Day Premarket Approval (PMA) Supplements
and 75-Day Humanitarian Device Exemption (HDE) Supplements for Manufacturing Method or
Process Changes- Guidance for Industry and FDA Staff”,2 regarding “changes FDA believes
may qualify for a 30-day notice and the changes that generally do not qualify.” The guidance
includes an illustrative list of manufacturing procedure changes or changes to the methods of
manufacture, that when they affect the safety and effectiveness of the device, would likely
qualify for a 30-day notice, such as “a change that adds a new cleanroom to existing
manufacturing space.” The list also includes that a 30-day notice may be appropriate for a
relocation of a formulation room within a manufacturing facility. The guidance explains that
“existing manufacturing space can include newly constructed space or buildings provided that
they are included under a single Firm Establishment Identifier (FEI). The guidance further
includes examples of changes FDA believes do not qualify for submission as a 30-day notice,
such as “a change in …manufacturing/sterilization site of a finished device.”
III. Scope
This guidance document describes the decision-making steps that we recommend you follow to
determine whether a PMA supplement should be submitted when you intend to change the
manufacturing site (including a change to the processing, packaging, or sterilization site) of your
legally marketed PMA-approved device. This guidance also discusses general factors FDA
intends to consider to determine whether a preapproval inspection is necessary before approval
of the PMA supplement.
This guidance document describes situations where a change in manufacturing site should be
submitted in a PMA manufacturing site change supplement. For guidance on what changes are
appropriate for reporting through other types of PMA submissions , please see the specific
guidance documents listed in Section VI, “Resources.”
Please note that this guidance only applies to a manufacturer of a device with an approved PMA,
a product development protocol, or a humanitarian device exemption (HDE). This guidance
does not address manufacturing site changes for devices cleared under premarket notification
(510(k)) submissions, granted premarket authorization through the De Novo pathway, or
approved and distributed as part of an investigational device exemption (IDE).
This guidance uses the term “site” to encompass both establishments and facilities.
“Establishment” and “facility” are not defined in 21 CFR Part 814. For purposes of this
2 For futher information on 30-day notices, 135-day PMA supplements, and 75-day HDE supplements for
manufacturing or process changes, please refer to this guidance, available at
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080194
.pdf

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guidance, FDA is using the term “establishment” as defined in 21 CFR 807.3(c), which means a
place of business under one management at one general physical location at which a device is
manufactured, assembled, or otherwise processed. FDA is defining the term “facility” for
purposes of this guidance to mean the physical structures or buildings within an “establishment.”
IV. Definitions
Unless otherwise specified, the terms below are defined as follows for purposes of this guidance
only.
• 	Components: A medical device component is any raw material, substance, piece, part,
software, firmware, labeling, or assembly which is intended to be included as part of the
finished, packaged, and labeled device. (21 CFR 820.3(c)) A medical device component
is considered an incomplete part of the finished medical device. Additionally, a
component is not separately distributed (i.e., not sold or available separately) to
consumers/end users, and is only sold to the manufacturer to be incorporated into the
finished medical device.
• 	Establishment: A place of business under one management at one general physical
location at which a device is manufactured, assembled, or otherwise processed (21 CFR
807.3(c)).
• 	Facility: The physical structures or buildings within an establishment.
• 	FDA Establishment Identifier (FEI):3 Number used by FDA in the identification of
registered establishments. A unique FEI is typically assigned to each business or entity
that performs activities subject to FDA jurisdiction. Since the year 2000, FEIs have been
issued with 10 digits.
• 	Finished Device: Any device or accessory to any device that is suitable for use or
capable of functioning, whether or not it is packaged, labeled, or sterilized (21 CFR
820.3(l)). Additional information on accessories can be found in the guidance, “Medical
Device Accessories - Describing Acessories and Classification Pathways4.”
• 	Manufacturing Site: A facility or establishment used to manufacture, process, or
package a finished device including an accessory of any finished device.
• 	No Action Indicated (NAI): Indicates no Quality System deficiencies, or Quality
System deficiencies of a quantity or type to conclude that there is a minimal probability,
in light of the relationship between quality system deficiencies observed and the
particular device and manufacturing process involved, that the establishment will produce
nonconforming or defective finished devices; this term is generally synonymous with a
Situation II inspection, in which FDA informs the establishment of any objectionable
findings, but generally does not initiate administrative or regulatory action. Situation II
3 For more information on how FDA assigns FEI numbers, please refer to the agency’s Field Management
Directives at http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/.
4 https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm429672.pdf

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inspection is defined in Part V of FDA’s Compliance Program 7382.845, “Inspection of
Medical Device Manufacturers5 .”
• 	Official Action Indicated (OAI): Indicates one or more major deficiencies with the
Quality System regulation such that FDA is prepared to initiate administrative and/or
regulatory action, including, but not limited to, issuance of a warning letter, injunction,
detention, seizure, civil money penalty, or prosecution; this term is synonymous with the
definition of a Situation I inspection. Situation I inspection is defined in Part V of FDA’s
Compliance Program 7382.845, “Inspection of Medical Device Manufacturers6 .”
• 	PMA Supplement (21 CFR 814.39(a)): After FDA’s approval of a PMA, an applicant
shall submit a PMA supplement for review and approval by FDA before making a change
affecting the safety or effectiveness of the device for which the applicant has an approved
PMA. The only exception to this requirement is if the change is a modification to the
manufacturing procedure or method of manufacture that affects safety or effectiveness
that does not require submission of a PMA supplement and is eligible for a 30-day notice.
While the burden for determining whether a supplement is required is primarily on the
PMA holder, changes for which an applicant shall submit a PMA supplement include, but
are not limited to, the following types of changes if they affect the safety or effectiveness
of the device:
(1) New indications for use of the device.
(2) Labeling changes.
(3) The use of a different facility or establishment to manufacture, process, or package
the device.
(4) Changes in sterilization procedures.
(5) Changes in packaging.
(6) Changes in the performance or design specifications, circuits, components,
ingredients, principle of operation, or physical layout of the device.
(7) Extension of the expiration date of the device based on data obtained under a new or
revised stability or sterility testing protocol that has not been approved by FDA.
• 	Site Change Supplement: A PMA supplement that relates to the use of a different
facility or establishment to manufacture, process, or package the device. There is no user
fee required for a site change supplement; for more information regarding user fees refer
to the guidance “User Fees and Refunds for Premarket Approval Applications and Device
Biologics License Applications”7.
• 	Voluntary Action Indicated (VAI): Indicates Quality System deficiencies of a quantity
or type to conclude that there is a minimal probability, in light of the relationship between
quality system deficiencies observed and the particular device and manufacturing process
involved, that the establishment will produce nonconforming or defective finished
5 The Compliance Program Guidance Manual for Program 7382.845 can be found at:
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM244277
.pdf
6 See supra n. 6.
7https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM34563
3.pdf

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devices; generally synonymous with a Situation II inspection, in which FDA informs the
establishment of any objectionable findings, but generally does not initiate administrative
or regulatory action.
• 	30 Day Notice: A submission to FDA for changes deemed to be a modification in a
manufacturing procedure or method of manufacturing of a PMA approved device.
(Section 515(d)(5)(A) of FD&C Act; 21 CFR 814.39(f)).
V. Submissions for Manufacturing Site Changes
A. 	What is a manufacturing site change and when should it
be submitted as a site change supplement versus a 30-Day Notice?
FDA has received questions on a variety of scenarios that might constitute using a different site
to manufacture, process, or package a device under 21 CFR 814.39(a)(3). A typical scenario
involves moving the site in which manufacturing activities take place. Other scenarios involve
expanding an existing site, building a new facility or establishment, or moving equipment within
a facility. Table 1 in this guidance is intended to address various manufacturing site changes that
may fall under these scenarios. The table describes when a particular scenario would be
considered “use [of] a different facility or establishment” for which a manufacturer should file a
PMA site change supplement or when a scenario would be considered a “modification to
manufacturing procedures or methods of manufacture” that is eligible for a 30-day notice.
For purposes of this guidance, FDA intends to consider a different site for which a site change
supplement should be submitted to include: 1) where the site was not approved as part of the
original PMA or a PMA supplement; or 2) where the site(s) was approved as part of the original
PMA or PMA supplement, but only for the performance of different manufacturing activities.
Under these circumstances, the different site would have no experience with either the process or
the technology, or a similar process or technology, for manufacturing the same or a similar
device, and FDA would not have had the opportunity to evaluate the change because it would not
have been evaluated in any way in the PMA application. 	In such instances, we would consider
the change to constitute “the use of a different facility or establishment” under 21 CFR
814.39(a)(3) and the manufacturer should submit a 180-day PMA supplement if the change
affects the device’s safety or effectiveness (section 515(d)(5)(A)(i) of FD&C Act). FDA
recognizes that a manufacturing site change would rarely involve a completely new
manufacturing technology for which the firm has no experience or the manufacture of a
dissimilar device at the new site, but for completeness of defining the underlying principle for
what constitutes a different site, it is important for FDA to consider both the site’s familiarity
with the manufacturing technology and the similarity to the devices manufactured at the site.
An applicant should submit a 180-day PMA supplement for using a different site, as described
above, that affects the device’s safety or effectiveness, which is also referred to as a site change
supplement that FDA reviews within 180 days of receipt. See 21 CFR 814.39(a)(3), 814.39(c),
and 814.40. Similarly, HDE holders are required to submit a 75-day supplement, per 21 CFR
814.108 and 814.114. The site change supplement should clearly identify any manufacturing
location changes and any associated changes to the manufacturing resulting from the site change

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(e.g., new facility requires changes to the water filtration for manufacturing). Manufacturing
process changes that are not directly associated with the facility move should be submitted
separately (e.g., 30-Day Notice or PMA Annual Report per existing regulations and guidance)
and are not considered part of the manufacturing site change supplement. Refer to subsection B
for additional information on what should be submitted in a site change supplement. Approval of
the 180-Day PMA Supplement is needed before any manufacturing site change and related
changes can be implemented.
Certain changes in manufacturing sites may be submitted as 30-day notices if they are among the
sites already approved in the PMA, and if they are for performance of the same or similar
manufacturing activities and for the same or similar device as those at the PMA approved site. If
the previously approved site and its personnel use and have experience with similar technology
and processes for manufacturing a similar device, then the new manufacturing site would not be
considered “different” under 21 CFR 814.39(a)(3). Such a change would be considered a
“modification” to an existing manufacturing procedure or method of manufacturing, under 21
CFR 814.39(f), and the applicant would be eligible to submit a 30-day notice if the
manufacturing site change affects the device’s safety or effectiveness.
FDA does not consider the use of a new facility or establishment for the manufacture,
processing, or packaging of a component of a finished device to require a PMA supplement.8
Firms that manufacture components that do not also manufacture finished devices are not subject
to the QS regulation requirements, under 21 CFR 820.1(a), but these manufacturers are
encouraged to use appropriate provisions of 21 CFR Part 820 as guidance. The finished device
manufacturer ensures compliance with QS requirements through the application of purchasing
controls (21 CFR 820.50) and acceptance criteria (21 CFR 820.80) for all components purchased
or otherwise received. Thus, an applicant should submit a 30-day notice, under 21 CFR
814.39(f), for use of a new supplier of those components that are critical to the finished device’s
function, operation, or specifications, because such modifications to the manufacturing
procedures or methods affect the finished device’s safety or effectiveness. Manufacturing
changes to components that are not critical to the device’s function, operation or specifications
do not require firms to submit 	a site change supplement or a 30-day notice; however,these
changes must be reported in the Annual Report.9
Table 1 outlines the type of manufacturing site changes that FDA believes affect the device’s
safety or effectiveness as well as the type of submission that should be submitted to FDA.
Manufacturers are responsible for validating changes, as necessary, in accordance with the QS
regulations, whether or not a PMA supplement is submitted.
Table 1
8 Please note the definition of finished devices includes accessories.
9 See 21 CFR 814.39(b) and 814.84(b)(1).

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Type of Manufacturing Site Change that Affects
Device Safety or Effectiveness
Site Change
Supplement
30-Day
Notice10
1. 	Moving manufacturing, processing, or packaging
activities for a finished device from one site to a
new manufacturing site, both of which were
approved as part of the PMA application or a
PMA supplement for the subject device:
a. 	If the moved activities are already conducted
at the new manufacturing site. 
b. 	If the moved activities are not already
conducted at the new manufacturing site 
2. 	Moving manufacturing, processing, or packaging
activities for a finished device to a new
manufacturing site that was not part of the PMA
application or a PMA supplement for the subject
device.

3. 	Moving manufacturing, processing, or packaging
activities for a finished device from a contract
manufacturer included in the PMA application or
a PMA supplement to an in-house facility
previously approved in the PMA application or a
PMA supplement:
a. For activities already conducted in-house for
the finished device. 
b. For activities not already conducted in-house
for the finished device. 
4. 	Moving manufacturing, processing, or packaging
activities for a finished device from one facility
to another within the same establishment that has
the same FEI

5. 	Moving manufacturing, processing, or packaging
activities for a finished device into a building
nearby (e.g., an office park), and the new
building has a different FEI

6. 	Moving the manufacturing, processing, or
packaging activities for a finished device to a
contract manufacturer not approved as part of the
PMA or a PMA supplement.

10 For further information on 30-day notices, 135-day PMA supplements, and 75-day HDE supplements for
manufacturing method or process changes, please refer to this guidance, available at
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080194
.pdf

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Type of Manufacturing Site Change that Affects
Device Safety or Effectiveness
Site Change
Supplement
30-Day
Notice10
7. 	Moving the manufacturing or processing of a
component that is critical to the finished device’s
function, operation, or specification

Illustrative examples are provided below that correspond with each situation
identified in Table 1.
1. 	Moving manufacturing, processing, or packaging activities for a finished device from one
site to a new manufacturing site both of which were approved as part of the PMA application
or a PMA supplement for the subject device:
a. 	If the moved activities are already conducted at the new manufacturing site for the
device:
For example, ABC, an applicant, has two sites approved in the original PMA.
Both sites manufacture cardiovascular catheters. ABC plans to move and
consolidate both cardiovascular catheter manufacturing lines to one of the two
approved sites, which could affect the safety or effectiveness of the device. A 30-
day notice should be submitted.
b. 	If the moved activities are not already conducted at the new manufacturing site:
For example, ABC, an applicant, received approval of a PMA application that
included manufacturing cardiovascular catheters at the firm’s Any Town, NY site
and sterilizing them at the firm’s Somewhere, CA site. ABC now plans to move
the sterilization process into the Any Town, NY facility that manufactures the
catheters. However, this Any Town, NY facility has no previous experience with
this sterilization process for this device, and this move could affect the device’s
safety or effectiveness. A site change supplement should be submitted.
2. 	Moving manufacturing, processing, or packaging activities for a finished device to a site that
was not part of the PMA application or a PMA supplement for the subject device:
For example, DEF, an applicant, received approval to manufacture a spinal disc
replacement device at its site in Hometown, NY. DEF now plans to manufacture
the device at another site in Anywhere, CA. The Anywhere, CA, site was not
included in the PMA application for the subject device. A site change supplement
should be submitted.
3. 	Moving manufacturing, processing, or packaging activities in-house for a finished device
from a contract manufacturer included in the PMA application or a PMA supplement to a
facility previously approved in the PMA application or a PMA supplement for the subject
device:

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a. 	In-house from a contract manufacturer included as part of the PMA application or PMA
supplement for activities already conducted in-house for the finished device:
For example, DEF, the applicant, uses contract manufacturer ABC to perform
sterilization activities for DEF’s cardiac stent system which is manufactured at
DEF’s Hometown, NY facility. DEF also performs sterilization activities in-
house at the Hometown, NY facility for a previous version of the cardiac stent
system which was approved in the same PMA application. DEF plans on
terminating the contract with ABC and conducting sterilization activities in-house
at the Hometown, NY facility for the cardiac stent system. A 30-day notice
should be submitted for this change.
b. 	In-house from a contract manufacturer included as part of the PMA application or PMA
supplement for activities not already conducted in-house for the finished device:
For example, XYZ, an applicant, uses contract manufacturer ABC to perform
some of the manufacturing steps for XYZ’s hip implant. XYZ plans on moving
these manufacturing steps in-house. This change will require company XYZ to
perform one or more manufacturing steps that it does not currently perform in-
house for the PMA device. A site change supplement should be submitted.
4. 	Moving manufacturing, processing, or packaging activities for a finished device from one
facility to another within the same establishment (same FEI):
For example, ABC, an applicant, currently performs a manufacturing step in a controlled
environment (Class 100 clean room) in Building A. ABC plans to move that
manufacturing step and the clean room from Building A to Building B within the same
currently-approved establishment (i.e., same FEI number). A 30-day notice should be
submitted.
5. 	Moving manufacturing, processing, or packaging activities for a finished device into a
building nearby (e.g., an office park), and the new building has a different FEI:
For example, ABC, an applicant, manufactures a breast cancer companion diagnostic kit.
ABC plans to move the manufacturing of the breast cancer kit to a new building. The
new building will be at a different location and have a different FEI number. A site
change supplement should be submitted.
6. 	Moving the manufacturing, processing, or packaging activities for a finished device to a
contract manufacturer not approved as part of the PMA application or a PMA supplement for
the subject device:
For example ABC, an applicant, manufactures an extended wear contact lens. The PMA
was approved for ABC to ship the raw material buttons to a contract manufacturer for
finishing and packaging. The manufacturing of the extended wear contact lens is
performed by the contract manufacturer XYZ, Inc. ABC plans to move the
manufacturing of the extended wear contact lens to another contract manufacturer that
was not part of the PMA application or a PMA supplement. A site change supplement
should be submitted.

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11
7. 	Moving the manufacturing or processing of a component that is critical to the finished
device’s function, operation, or specification:
For example, ABC, an applicant, currently manufactures the filter component for
a slide preparation device. ABC plans to move the manufacturing of these filters
to another company, XYZ. XYZ was not part of ABC’s original PMA approval
for the device. A 30-day notice should be submitted because that component is
considered critical and the modification affects the device’s safety or
effectiveness. Note that this example would have the same outcome if the
component manufacturing was being moved to one supplier from another, or if
the component manufacturing was being moved in-house from a supplier.
For example, ABC, an applicant, uses contract manufacturer DEF to manufacture
the crystal oscillator, which is a component of ABC’s implantable defibrillator.
Now ABC would like to add a new company, GHI, as a second supply source for
the crystal oscillator. A 30-day notice should be submitted because that
component is considered critical and the modification affects the device’s safety
or effectiveness.
B. 	What should be submitted in the site change supplement?
Under 21 CFR 814.39(c), the PMA supplement must contain information needed to support the
use of a different facility or establishment to manufacture, process, or package the device. In
order to approve a site change supplement, the information submitted must show that, for the
different site, the methods used in, and the facilities or controls used for, the manufacture,
processing, and when relevant, packing and installation of the device conform to the
requirements of the QS regulation, 21 CFR Part 820. See sections 515(c)(1)(C), 515(d)(2)(C)
and 520(f) of the FD&C Act, 21 U.S.C. §§ 360e(c)(1)(C), 360e(d)(2)(C) and 360j(f). FDA
recommends that the following information be included in a site change supplement, if
applicable:11
1. 	A description of the device, intended use, and nature and purpose of the site change,
including a description of the manufacturing functions that will be performed at the
proposed site (e.g., assembly or incoming acceptance).
2. 	A diagram of the proposed new manufacturing, processing, packaging, or distribution
site(s).
3. 	A flow diagram that identifies the steps involved in the manufacture, processing,
packaging, or distribution of the device under review at the proposed site(s).
11 For further information on manufacturing changes that may qualify for a 30-day notice please refer to FDA’s
final guidance, 30-Day Notices, 135-Day Premarket Approval (PMA) Supplements and 75-Day Humanitarian
Device Exemption (HDE) Supplements for Manufacturing Method or Process Changes
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080194
.pdf

Contains Nonbinding Recommendations
12
4. 	A description of the equipment and processes that would be affected by the site change.
5. 	A list of any standards used in the new manufacturing processes, if applicable.
6. 	The process validation or revalidation master plan for the site, if appropriate (including
validation of software that is used as part of the production or quality system where
applicable, see 21 CFR 820.70(i)).
7. 	A list of processes at the new site that you do not plan to validate but will verify by
inspection and test.
8. 	The process validation or revalidation procedures (and reports, if applicable):
a. 	For site change supplements for which it would be likely that FDA would conduct a
preapproval inspection based on the information outlined in Section C below, we
recommend that you provide the process validation or revalidation protocols for the
processes requiring validation. If a determination has been made that only a subset of
the process validation activities needs to be completed, then the rationale and
supporting data for that decision should be supplied. For additional information on
process validation, please see “Quality Management Systems – Process Validation
Guidance12.” When available, you should provide a copy of any completed
validation reports13. 	All validation activities should be completed before the
scheduling of an inspection. Accordingly, you should provide a date when your
validation activities will be complete and you will be ready for inspection.
b. 	If FDA decides not to conduct a preapproval inspection based on the information
outlined in Section C below, we will likely recommend the applicant to provide the
process validation or revalidation protocols and completed reports for all the
processes that require validation.
9. 	The procedures for environmental and contamination controls, if such conditions could
adversely affect the device (21 CFR 820.70). If this involves a large number of
procedures, a sample of the most relevant procedures would be sufficient.
10. If different from the original PMA, any procedures that explain how inspection,
measuring, and test equipment are routinely calibrated, inspected, checked, and
maintained (21 CFR 820.72). If this involves a large number of procedures, a sample of
the most relevant procedures would be sufficient. If procedures are the same as those
12 Previously posted by the Global Harmonization Task Force (GHTF), this process validation guidance is now
posted on the International Medical Devices Regulators Forum (IMDRF) website at
http://www.imdrf.org/docs/ghtf/final/sg3/technical-docs/ghtf-sg3-n99-10-2004-qms-process-guidance-04010.pdf.
13 See Quality System Information for Certain Premarket Application Reviews; Guidance for Industry and FDA
Staff
(https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070899.
pdf)
for more information regarding documentation of process validation activities.

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contained and approved in the original PMA, you should provide a statement indicating
this.
11. If the manufacturing site change results in the use of a different supplier or contract
manufacturer:
a. 	Provide or reference the current purchasing control procedures detailing the
supplier evaluation process and describe how you will determine the type and
extent of control that is to be exercised over the suppliers. The procedures should
address:
(1) The quality controls that are established for the supplier, how those quality
controls are evaluated, and how the quality controls are monitored.
(2) The communication method for ensuring that you and the supplier fully
understand all of the controls that are applicable to the supplier.
(3) The change control mechanism utilized for ensuring adequate control over
design and process related changes made by both you and the supplier.
(4) How you maintain records of acceptable suppliers and how you address the
purchasing data approval process.
(5) How you balance purchasing assessment and receiving acceptance to ensure
that products conform to specified requirements.
b. 	Provide the specific documentation for any supplier, vendor, or contract
manufacturer that establishes how you applied the purchasing controls (21 CFR
820.50) and acceptance activities requirements (21 CFR 820.80) to ensure the
specific products and services purchased or received conform to specified
requirements.14
12. The procedures for the incoming acceptance activities at the subject manufacturing site, if
different from the procedures contained and approved in the original PMA. If procedures
are the same as those contained and approved in the original PMA, you should provide a
statement indicating this.
13. The procedures for the final acceptance activities at the subject manufacturing site, if
applicable and different from the procedures contained and approved in the original
PMA. If procedures are the same as those contained and approved in the original PMA,
you should provide a statement indicating this.
14 	See comments 99, 106, and 109 in the preamble to the Quality System Regulation (61 FR 52602) for additional
guidance on (1) balancing purchasing controls and acceptance and receiving activities, (2) balancing supplier
and manufacturer quality controls and assurance measures, and (3) the term “quality requirements.”
http://frwebgate.access.gpo.gov/cgi-bin/getpage.cgi?position=all&page=52624&dbname=1996_register

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C. 	Determining whether an inspection may be needed.
As with a premarket approval application, a supplemental premarket approval application may
be approved if it meets the applicable statutory and regulatory requirements. One such
requirement is that the methods used in, or the facilities or controls used for, the manufacture,
processing, packaging, storage or installation of a device conforms to the requirements of section
520(f) of the FD&C Act. A preapproval inspection for a site change supplement may be
necessary for FDA to find that the methods used in, or the facilities or controls used for, the
manufacture, processing, packaging, storage or installation of the device conform to the
requirements of the QS regulation, 21 CFR Part 820. See sections 515(c)(1)(C), 515(d)(2)(C)
and 520(f) of the FD&C Act, 21 U.S.C. §§ 360e(c)(1)(C), 360e(d)(2)(C) and 360j(f).
CDRH and CBER generally determines whether to conduct an inspection of a new site
associated with a site change supplement based upon the following factors:
• 	the dates of the last inspections of the current site and the new site;
• 	the classifications of the last inspections of the current site and the new site;
• 	the relevance of the last QS regulation inspection to the moved manufacturing,
processing, or packaging activities (e.g., whether similar products or processes were
inspected);
• 	a review of relevant recalls and adverse events, associated with manufacturing processes
for devices manufactured, processed or packaged at this site; and
• 	the risk to the safety or effectiveness of the device associated with the manufacturing
activities performed at the new site.
CDRH and CBER review the inspectional record to determine the classification of previous
inspections. Inspections can be classified as Official Action Indicated (OAI), Voluntary Action
Indicated (VAI), or No Action Indicated (NAI). OAI is synonymous with the definition of a
Situation I inspection as defined in Part V of FDA’s Compliance Program 7382.845, “Inspection
of Medical Device Manufacturers.”15 Situation I indicates one or more major deficiencies with
the Quality System regulation such that FDA is prepared to initiate administrative and/or
regulatory action, including, but not limited to, issuance of a warning letter, injunction,
detention, seizure, civil money penalty, or prosecution. NAI and VAI classifications are
generally synonymous with a Situation II inspection, which indicates Quality System
deficiencies of a quantity or type to conclude that there is a minimal probability, in light of the
relationship between quality system deficiencies observed and the particular device and
manufacturing process involved, that the establishment will produce nonconforming or defective
finished devices. In Situation II, FDA informs the establishment of any objectionable findings,
but generally does not initiate administrative or regulatory action.
CDRH and CBER intend to consider the factors outlined above in determining the need for an
inspection at the time of review. For example, when the new site has not been inspected or the
last inspection of either the current or the new site was classified as OAI, then FDA intends to
15 See supra n. 6.

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15
conduct an inspection of the new site if CDRH or CBER reviews the site change supplement and
concludes that it is approvable pending a non-violative (Situation II) inspection. Manufacturers
may contact the appropriate office to discuss whether a pre-approval inspection may be required;
the pre-submission process may be utilized for these interactions, if appropriate.16
VI. 	Resources
The following are resources that may be of assistance in developing the content of your site
change supplement or 30-day notice, preparing for an inspection, or in performing process
validation:
1. 	Quality System Information for Certain Premarket Application Reviews; Guidance for
Industry and FDA Staff, available at https://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-meddev-gen/documents/document/ucm070899.pdf
https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocumen
ts/UCM070899
2. 	Guidance for Industry and FDA Staff; The Review and Inspection of Premarket Approval
Application Manufacturing Information and Operations, available at
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-
gen/documents/document/ucm077795.pdf
3. 	Guidance for Industry; Process Validation: General Principles and Practices, available at
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.
4. 	Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality
System Regulation, 61 FR 52602, October 7, 1996, available at
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequire
ments/QualitySystemsRegulations/ucm230127.htm.
5. 	Guidance for Industry and FDA Staff: 30-Day Notices, 135-Day Premarket Approval
(PMA) Supplements, and 75-Day Humanitarian Device Exemption (HDE) Supplements
for Manufacturing Method or Process Changes, available at
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidan
ceDocuments/UCM080194.pdf
6. 	OEI (Official Establishment Inventory) Development and Maintenance Procedures,
available at
http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm096034.htm.
7. 	Compliance Program Guidance Manual, Inspection of Medical Device Manufacturers.
Program 7382.845, available at
16 For more information on requests for feedback on medical device submissions, please refer to FDA’s final
guidance, Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with
Food and Drug Administration Staff, available at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-
meddev-gen/documents/document/ucm311176.pdf

Contains Nonbinding Recommendations
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http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/UCM244277.pdf.
8. 	Guidance for Industry and FDA Staff: Modifications to Devices Subject to Premarket
Approval (PMA) - The PMA Supplement Decision-Making Process (2008), available at
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-
gen/documents/document/ucm270606.pdf
9. 	Annual Reports for Approved Premarket Approval Applications (PMA) – Guidance for
Industry and Food and Drug Administration Staff, available at
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-
gen/documents/document/ucm089398.pdf
10. User Fees and Refunds for Premarket Approval Applications and Device Biologics
License Applications, available at https://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-meddev-gen/documents/document/ucm345633.pdf