Contains Nonbinding Recommendations 
 
 
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  
Food and Drug Administration Staff  
 
Document issued on December 16, 2019. 
 
Document originally issued on April 13, 2011. 
 
 
 
For questions regarding this document, contact the ORP:  Office of Regulatory Programs/Division of 
Regulatory Programs 1: Submission Support at 301-796-5640.   
 
For questions regarding submissions to the Center for Biologics Evaluation and Research, contact 
CBERs Office of Communication, Outreach and Development (OCOD) at 1-800-835-4709 or 240-402-
8010, ocod@fda.hhs.gov. 
 
 
 
 
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 
http://www.regulations.gov. Submit written comments to the Division of Dockets Management, 
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 
20852.  Identify all comments with the docket number FDA-1998-D-0281. 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 a copy of the guidance.  Please include the document 
number 1687 and complete title of the guidance in the request. 
 
CBER 
Additional copies are available from the Center for Biologics Evaluation and Research (CBER), 
Office of Communication, Outreach, and Development (OCOD), 10903 New Hampshire Ave., 
WO71, Room 3128, Silver Spring, MD 20903, or by calling 1-800-835-4709 or 240-402-8010, 
by email, ocod@fda.hhs.gov, or from the Internet at  
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics.     Contains Nonbinding Recommendations 
 
 
 
Table of Contents 
 
 
I.  Introduction ........................................................................................................................................ 4 
II.  What Changes Qualify for Submission of a 30-Day Notice? ......................................................... 5 
III.  What Changes Do Not Qualify for Submission of a 30- Day Notice? ........................................... 8 
IV.  Contents of a 30-Day Notice .............................................................................................................. 9 
V.  Action on a 30-Day Notice, 135-Day PMA Supplement, or 75-Day HDE Supplement ............. 10 
VI.  Submission of a 30-Day Notice........................................................................................................ 11 
VII.  Exceptions To User Fees For 30-Day Notices ................................................................................ 11    Contains Nonbinding Recommendations 
 
 
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  
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 
 
Section 515(d)(6)(A) of the Federal Food, Drug, and Cosmetic Act (the Act) provides that PMA 
supplements are required for any change to a device subject to an approved application that 
affects safety or effectiveness, unless such change is a modification in a manufacturing 
procedure or method of manufacturing.1 The Act states that changes in manufacturing 
procedures or method of manufacturing that affect safety or effectiveness require a 30-day 
notice. Where FDA finds such notice inadequate, FDA will inform the applicant that a 135-day 
PMA supplement or 75-day HDE supplement must be submitted.2  An HDE holder must submit 
supplements in accordance with PMA requirements under 21 CFR 814.39, except that requests 
for a new indication for use of a HUD must comply with 21 CFR 814.110.3  However, the 
timeframe for reviewing HDE supplements is 75 days.4 Thus, changes that would require a 135-
day supplement for a PMA would require a 75-day supplements for an HDE. The purpose of this 
                                                           
1 21 U.S.C. 360e(d)(6)(A) 
2 21 CFR 814.39(f), 814.108 
3 21 CFR 814.108 
4 21 CFR 814.108 and 814.114. 
  4    Contains Nonbinding Recommendations 
 
 
document is to provide guidance on the changes FDA believes may qualify for the 30-day 
notice and the changes that generally do not qualify. 
 
The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) (P.L. 107-250) 
amended the FD&C Act to provide FDA new responsibilities and authorities.  One significant 
provision of the Act, as amended by MDUFMA, Section 738,5 required FDA to collect user 
fees for certain premarket submissions or supplements received on or after October 1, 2002.  
MDUFMA established user fee rates that varied depending on the type of submission. 
However, under MDUFMA, 30-day notices were not among the file types that were subject to 
user fees.  The Food and Drug Administration Amendments Act of 2007 (FDAAA) (P.L. 110-
85) later amended the Act to require user fees for 30-day notices.6 
 
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 guidances means that something is suggested 
or recommended, but not required. 
 
II.  What Changes Qualify for Submission of a 30-Day 
Notice? 
 
Changes, which affect the safety or effectiveness of the device, that may qualify for submission 
as a 30-day notice, are: 
 
  changes to the manufacturing procedure; or 
 
  changes in method of manufacture; 
 
When these changes, however, also alter performance or design specifications or the designated 
physical or chemical specifications of the finished device, a 30 day notice is not appropriate.7  
In these cases, a PMA holder should submit a 180-day PMA supplement8 or a real-time review 
PMA Supplement,9 as appropriate.  Similarly, in these instances, an HDE holder must submit a 
75-day HDE supplement.10  
Examples below are manufacturing procedure changes or changes to the methods of 
manufacture, that when they affect the safety or effectiveness of the device, would likely qualify 
for a 30-day notice. 
                                                           
5 All references to Sections 738 in this guidance document refer to Section 738 of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act). 21 U.S.C. 379j. 
6 21 U.S.C. 379j(a)(2)(A)(vi) 
7 Changes in the performance or design specifications, circuits, components, ingredients, principle of operation, or 
physical layout of the device, must be submitted as a PMA supplement.  21 CFR 814.39(a)(6). 
8 A 180-day supplement is a supplement to an approved premarket application or premarket report under section 
515 that is not a panel-track supplement and requests a significant change in components, materials, design, 
specification, software, color additives, or labeling. 21 U.S.C. 379i(4)(C). 
9 A real-time supplement is a supplement to an approved premarket application or premarket report that requests a 
minor change to the device, such as a minor change to the design of the device, software, sterilization, or labeling, 
and for which the applicant has requested and the agency has granted a meeting or similar forum to jointly review 
and determine the status of the supplement.  21 U.S.C. 379i(4)(D). 
10 21 CFR 814.108 
  5    Contains Nonbinding Recommendations 
 
 
 
Sterilization Process Parameters within the Same Facility 
Generally, a 30-day notice may be appropriate for changes in: 
 
  sterility dose auditing; 
o
 
  aeration time used at sterilization site; 
o
 
Automating Existing Processes 
Generally, a 30-day notice may be appropriate when you change from: 
 
  a manual cutting process to an automated cutting process; 
o
 
  manually controlled machining to manufacturing processes that use computer 
o
numeric control (CNC) machining; 
 
  manual sewing to automation of the sewing process; 
o
 
  an existing manual soldering process to adding an alternate automated soldering 
o
process for joining the high voltage capacitor wires to the high voltage printed 
circuit board assembly (PCBA) connector pads. 
 
Joining Processes 
Generally, a 30-day notice may be appropriate for changes in: 
 
  the resistance weld that bonds the feedthrough wire to the implantable pulse 
o
generators (IPGs) connector wire to add a spot laser weld; 
 
  a manufacturing process change from a resistance weld to a laser weld; 
o
 
  the bonding equipment to replace existing equipment with a different model heat 
o
bonder. (Note:  A validated change that replaces the equipment with identical 
equipment that uses the same parameters as originally validated would not require 
a 30-day notice.) 
 
Cleaning Methods Used to Remove Manufacturing Materials 
Generally, a 30-day notice may be appropriate when you: 
 
  change the wash process for the Printed Circuit Board Assembly (PCBA) 
o
sequence to increase the efficiency of the process and to reduce cost; 
 
  replace the current manual cleaning process for removing residual manufacturing 
o
materials from equipment with a semi-automatic substrate washer. 
 
Manufacturing Materials 
Generally, a 30-day notice may be appropriate for changes to: 
 
  machining lubricants; 
o
 
  the flux used for solder rework. 
o
 
Environmental Conditions of the Manufacturing, Storage or Distribution Facilities 
Generally, a 30-day notice may be appropriate for: 
  6    Contains Nonbinding Recommendations 
 
 
11
  a change that adds a new cleanroom to existing manufacturing space ; 
o
 
  a change from an ISO Class 4 environment to an ISO Class 5 environment; 
o
 
  a relocation of a formulation room within a manufacturing facility. 
o
 
Suppliers of Components, Materials or Services, where Specifications Are Unchanged 
Generally, a 30-day notice may be appropriate when: 
 
  using an additional supplier for the laser welding of components; 
o
 
  adding a raw material supplier; 
o
 
  adding an alternate supplier for the UV chromophore for an intraocular lens; 
o
 
  making a change in sterilization test site for sterilization test samples. 
o
 
These changes should be submitted as 30-day notices only when the material was critical to 
the performance of the device, as determined by the manufacturer. If the material is not 
critical to the performance of the device, then any change should be submitted as part of the 
periodic report (often referred to as the annual report).12  
 
Note, however, that if a manufacturing change involves adding a second supplier of a 
critical component, and the specifications of that component are different, a 30-day notice is 
not appropriate because the specifications have changed. 21 CFR 814.39(a)(6). A PMA 
holder should submit a 180-day PMA supplement or a real-time review PMA Supplement, 
as appropriate.  Similarly, in these instances, an HDE holder should submit a 75-day HDE 
supplement. 21 CFR 814.108. 
 
For the purposes of this guidance document, a supplier is anyone that is independent from 
the manufacturers quality management system that provides the manufacturer components, 
materials, or services. This includes a supplier that may be part of the manufacturers 
organization but operates under a separate quality management system. (i.e., this supplier is 
known as an internal supplier).  In other words, if the supplier is not a part of the 
manufacturers internal audit (quality audit) scope, then the supplier is under a separate 
quality management system and is considered an internal supplier. Internal suppliers are to 
be controlled in a similar way as external suppliers are controlled and 30-day notices would 
be needed for changes that would ordinarily be submitted for supplier changes. 
 
Quality Control Testing 
Generally, a 30-day notice may be appropriate for changes to quality control testing used on 
incoming components, raw materials, the in-process device, or the finished device, for 
example: 
 
  performing end-product pyrogen testing on non-sterile samples prior to sterilization; 
o
  eliminating certain in-process or final device tests, to eliminate test redundancy, 
o
waste, or use test samples selected during processing more efficiently; 
 
                                                           
11 For the purposes of this guidance, existing manufacturing space can include newly constructed space or 
buildings provided that they are included under a single Firm Establishment Identifier (FEI). 
12 21 CFR 814.39(b)  
  7    Contains Nonbinding Recommendations 
 
 
  changing sample size in a bacterial endotoxin test assay; 
o
 
  removing a rejection criterion for component acceptance in an in-process inspection 
o
step; 
 
  adding inspection steps in direct response to field failures of the device. 
o
 
Type of Manufacturing Process 
Changing the type of process used, e.g., a change from machining a particular part to 
injection molding the part may be appropriate for submission as a 30-day notice. 
 
Changes that qualify for a "Special PMA Supplement - Changes Being Effected" under 21 CFR 
814.39(d)(2) for changes in quality controls or manufacturing process that add a new 
specification or test method, or otherwise provide additional assurance of purity, identity, 
strength, or reliability of the device can be submitted either as a "Special PMA Supplement - 
Changes Being Effected" or a 30-day notice. The manufacturing changes that may be reviewed 
as a Special PMA Supplement are generally those that add a step to the quality control or 
manufacturing process to enhance safety but do not impact effectiveness.  If efficacy is also 
affected, those changes should be submitted as a 30-day notice. 
 
The examples above are only illustrative and are not intended to be exhaustive.  Additional 
examples of changes appropriate for submission as 30-day notices may be found in the FDA 
guidance entitled, Modifications to Devices Subject to Premarket Approval (PMA) - The PMA 
Supplement Decision-Making Process.13  
 
III.  What Changes Do Not Qualify for Submission of a 30- 
Day Notice? 
 
Examples of changes FDA believes do not qualify for submission as a 30-day notice include 
any change in manufacturing needed to accommodate a change in: 
 
14
  manufacturing/sterilization site of a finished device ; 
 
  device design or performance specifications; 
 
  material specifications or 
 
  device operating software. 
 
FDA recommends that submissions for these changes be in the form of a 180-day PMA 
supplement, real-time supplement, site-change supplement, or a 75-day HDE supplement, as 
appropriate. For additional information on the appropriate supplement type, refer to the FDA 
guidance Modifications to Devices Subject to Premarket Approval (PMA) - The PMA 
Supplement Decision-Making Process15 and for additional information regarding site change 
                                                           
13 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/modifications-devices-subject-
premarket-approval-pma-pma-supplement-decision-making-process 
14 A finished device is defined in 21 CFR  820.3(l) as any device or accessory to any device that is suitable for 
use or capable of function, whether or not it is packaged, labeled, or sterilized. 
15 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/modifications-devices-subject-
  8    Contains Nonbinding Recommendations 
 
 
supplements, refer to the FDA guidance document Manufacturing Site Change Supplements: 
Content and Submission.16  
 
Changes to the manufacturing procedure or method of manufacturing that do not affect the 
safety or effectiveness of the device must be submitted in the periodic report, that is usually 
referred to as an annual report.17 Devices subject to premarket approval under section 515 of 
the Act are also subject to periodic report requirements imposed by the PMA approval order.18 
FDA typically specifies that a PMA holder submit a report one year from the date of approval 
of the original PMA and annually thereafter. Therefore, the periodic report is usually referred to 
as an annual report. For additional information regarding annual reports, refer to the FDA 
guidance document Annual Reports for Approved Premarket Approval Applications 
(PMA).19 
 
If a 30 day-day notice contains device design or labeling changes in addition to manufacturing 
changes, then the submission will automatically be converted to a 180-day PMA or 75-Day 
HDE supplement and reviewed accordingly.20  
 
IV.  Contents of a 30-Day Notice 
 
A 30-day notice must contain21: 
 
  a description of the change (any illustrative pictures should also be included); 
o
 
  a summary of the data or information supporting the change, e.g., a few concise pages 
o
summarizing the key results; and 
 
  a statement that the change has been made under the requirements of  520(f) of the 
o
FDCA and 21 CFR. Part 820. 
 
A 30-day notice should also contain: 
 
  a description of the device; 
o
 
  identification of the manufacturing facilities where the change will be implemented; 
o
 
  reason for the change, including a description of any adverse events or field failures that 
o
have occurred; 
 
  appendices of supporting data, where appropriate. 
o
 
The summary of the data or information supporting the change, should include: 
 
  a summary of the procedures established for the identification, documentation, 
o
validation, review, and approval of the manufacturing changes submitted in the 30- day 
notice; 
                                                           
premarket-approval-pma-pma-supplement-decision-making-process  
16 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/manufacturing-site-change-
supplements-content-and-submission-0  
 
17  21 CFR 814.39(b), 814.126(b)(1) 
18 21 CFR 814.82(a), 21 CFR 814.84(b) 
19 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/annual-reports-approved-
premarket-approval-applications-pma  
20 21 CFR 814.39(a) 
21 21 U.S.C. 360e(d)(6)(A)(i) and 21 CFR  814.39(f). 
  9    Contains Nonbinding Recommendations 
 
 
 
  the statistical rationale for the sampling method, if you plan to verify the changed 
o
processes by routine sampling and independent measurement; 
 
  a description of how you will monitor and control any manufacturing process you intend 
o
to change; 
 
  a summary of the completed validation study that demonstrates that the manufacturing 
o
change can be made without significantly changing the operation of the final device.  
This summary should  include: 
 
  a description of the acceptance criteria; 
  information on how, using valid statistical methods, you analyzed the test data; 
 
  information that describes the statistical rationale for sample sizes; 
 
  a list of any deviations that occurred; and 
 
  a determination of the impact of the deviation on the results; 
 
  an explanation of how change control procedures were implemented, including 
whether you modified the manufacturing or quality control instructions, or the 
manufacturing specifications. 
 
In addition, you should include a summary of how purchasing control procedures were 
implemented to evaluate any new supplier or contractor, if the manufacturing change involves: 
 
  changes in suppliers of components or raw materials that are critical to the performance 
of the device; or 
 
  the use of a new contractor for a manufacturing process or quality control testing. 
 
You should also describe the type and extent of control to be exercised over the component or 
raw material, including specifications for the incoming material and a description of in-coming 
acceptance activities.  Additionally, you should describe any testing that was completed to 
evaluate the use of the component or material and include a summary of the data.  Note:  If the 
contract manufacturer is manufacturing a finished device as defined in 21 CFR 820.3(l), then a 
30-day notice is not appropriate and the change should be submitted as a manufacturing site 
change supplement.22  
 
V.  Action on a 30-Day Notice, 135-Day PMA Supplement, 
or 75-Day HDE Supplement 
 
If the change qualifies for a 30-day notice and you have submitted complete information in the 
30-day notice to FDA, you may distribute the device 30 days after the date on which FDA 
received the notice, unless FDA notifies you with those 30 days that the notice is inadequate. 
 
However, if the information you have submitted is not adequate, within 30 days of receipt FDA 
will inform you via email23 or letter that a 135-day PMA supplement or for HDE holders, a 75- 
                                                           
22 21 CFR 814.39(a)(3) 
23 For additional information about email communications with CBER, please see SOPP 8119: Use of Email for 
Regulatory Communications, available at 
  10    Contains Nonbinding Recommendations 
 
 
day HDE supplement is needed and shall describe additional information or action that is 
required for acceptance of that change.24   
 
If no action occurs within 30 days of receipt of your 30-day notice and payment of the user fee, 
you may distribute the device without further action from FDA.25  
 
VI.  Submission of a 30-Day Notice 
 
To facilitate the review of your 30-day notice, you should clearly and conspicuously indicate 
in your cover letter that the submission is a 30-day notice; large type and bold face are 
desirable, e.g., 30-DAY NOTICE.  Failure to properly identify the submission may cause 
FDA to process it as a supplemental PMA or HDE. 
 
Applicants are requested to submit one electronic copy (eCopy) to the appropriate Center: 
 
  For devices regulated by CDRH, send it to the current address displayed on the 
website http://www.fda.gov/cdrhsubmissionaddress. 
 
  For devices regulated by CBER, send it to the current address displayed on the website 
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/
CBER/ucm385240.htm.   
 
The eCopy must be accompanied by a single paper copy of your signed cover letter.26 The 
current fee structure for 30-day notices may be found at: 
https://www.fda.gov/ForIndustry/UserFees/MedicalDeviceUserFee/ucm452519.htm. 
 
VII. Exceptions To User Fees For 30-Day Notices 
 
In accordance with Section 738(a)(2)(B) of the Act, the submissions listed below are not 
subject to user fees. 
 
  HDEs and HDE supplements, including HDE supplements that are reported as 30-day 
notices; 
 
  any PMA or PMA supplement intended solely for a pediatric population; or 
 
  PMAs or PMA supplements submitted by a state or federal government entity unless 
the device involved is to be distributed commercially. 
                                                           
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/uc
m109645.htm   
24 21 CFR 814.39(f), 814.108 
25 Section 515(d)(6)(A)(ii) and 738(a)(2)(A)(vi) of the Act. 
26 Please refer to the FDA guidance, eCopy Program for Medical Device Submissions 
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ecopy-program-medical-device-
submissions), for additional information on eCopy program. 
  11