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 
 
      
 
 
 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
 
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. 
  
 
 
          Contains Nonbinding Recommendations 
 
 
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.   WHAT IS A MANUFACTURING  SITE CHANGE AND WHEN SHOULD IT BE SUBMITTED AS A SITE CHANGE 
SUPPLEMENT VERSUS A 30-DAY NOTICE? ............................................................................................... 6 
B.   WHAT SHOULD BE SUBMITTED IN THE SITE CHANGE SUPPLEMENT? ....................................................... 11 
C.  DETERMINING WHETHER AN INSPECTION MAY BE NEEDED. ................................................................... 14 
D.  ADDITIONAL RESOURCES ...................................................................................................................... 15 
          Contains Nonbinding Recommendations 
 
 
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 FDAs 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. 
 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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 devices 
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 
        1  Contains Nonbinding Recommendations 
 
 
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 devices 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 Agencys 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 firms 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. 
        2  Contains Nonbinding Recommendations 
 
 
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 
        3  Contains Nonbinding Recommendations 
 
 
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 agencys 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   
        4  Contains Nonbinding Recommendations 
 
 
inspection is defined in Part V of FDAs 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 FDAs 
Compliance Program 7382.845, Inspection of Medical Device Manufacturers6. 
 
  PMA Supplement (21 CFR 814.39(a)): After FDAs 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 Applications7. 
 
  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    
        5  Contains Nonbinding Recommendations 
 
 
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 devices 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 sites 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 devices 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 
        6  Contains Nonbinding Recommendations 
 
 
(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 devices 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 devices 
function, operation, or specifications, because such modifications to the manufacturing 
procedures or methods affect the finished devices safety or effectiveness.  Manufacturing 
changes to components that are not critical to the devices 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 devices 
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).  
        7  Contains Nonbinding Recommendations 
 
 
Site Change  30-Day 
Type of Manufacturing Site Change that Affects 
Supplement   Notice10 
Device Safety or Effectiveness 
   
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  
 
 
        8  Contains Nonbinding Recommendations 
 
 
Site Change  30-Day 
Type of Manufacturing Site Change that Affects 
Supplement   Notice10 
Device Safety or Effectiveness 
   
7.  Moving the manufacturing or processing of a 
component that is critical to the finished devices     
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 firms Any Town, NY site 
and sterilizing them at the firms 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 devices 
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: 
        9  Contains Nonbinding Recommendations 
 
 
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 DEFs cardiac stent system which is manufactured at 
DEFs 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 XYZs 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. 
 
        10  Contains Nonbinding Recommendations 
 
 
7.  Moving the manufacturing or processing of a component that is critical to the finished 
devices 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 ABCs original PMA approval 
for the device.  A 30-day notice should be submitted because that component is 
considered critical and the modification affects the devices 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 ABCs 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 devices 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 FDAs 
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     
        11  Contains Nonbinding Recommendations 
 
 
 
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. 
        12  Contains Nonbinding Recommendations 
 
 
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   
 
        13  Contains Nonbinding Recommendations 
 
 
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 FDAs 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. 
        14  Contains Nonbinding Recommendations 
 
 
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 FDAs 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     
        15  Contains Nonbinding Recommendations 
 
 
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    
 
 
 
        16