Guidance for Industry and FDA Staff – 30-Day Notices, 135-Day Premarket Approval (PMA) Supplements and 75

Document issued on: April 13, 2011

This document supersedes 30-Day Notices and 135-Day PMA Supplements for Manufacturing Method or Process Changes, issued on February 19, 1998.

This document replaces the guidance entitled, “30-Day Notices and 135-Day PMA Supplements for Manufacturing Method or Process Changes,” issued February 19, 1998. This new guidance includes updates to reflect the current review process, additional examples of manufacturing changes that may be submitted under this program, and a discussion of user fees.

The Medical Device User Fee and Modernization Act of 2002 ( MDUFMA) (P.L. 107-250) amended the FDC Act to provide FDA new responsibilities and authorities. One significant provision of the Act, as amended by MDUFMA, Section 738,² 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. 21 U.S.C. 379j(a)(2)(A)(vi).

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.

3 In these cases, a PMA holder should submit a 180-day PMA supplement⁴ or a real-time review PMA Supplement,⁵ as appropriate. Similarly, in these instances, an HDE holder must submit a 75-day HDE supplement. 21 CFR 814.108.

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.

Sterilization Process Parameters within the Same Facility

Generally, a 30-day notice may be appropriate for changes in:

• sterility dose auditing;
• aeration time used at sterilization site;

Automating Existing Processes

Generally, a 30-day notice may be appropriate when you change from:

• a manual cutting process to an automated cutting process;
• manually controlled machining to manufacturing processes that use computer numeric control (CNC) machining;
• manual sewing to automation of the sewing process;
• an existing manual soldering process to adding an alternate automated soldering 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 generator’s (IPG’s) connector wire to add a spot laser weld;
• a manufacturing process change from a resistance weld to a laser weld;
• the bonding equipment to replace existing equipment with a different model heat 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) sequence to increase the efficiency of the process and to reduce cost;
• replace the current manual cleaning process for removing residual manufacturing materials from equipment with a semi-automatic substrate washer.

Manufacturing Materials

Generally, a 30-day notice may be appropriate for changes to:

• machining lubricants;
• the flux used for solder rework.

Environmental Conditions of the Manufacturing, Storage or Distribution Facilities

Generally, a 30-day notice may be appropriate for:

• a change that adds a new cleanroom to existing manufacturing space⁶;
• a change from an ISO Class 4 environment to an ISO Class 5 environment;
• a relocation of a formulation room within a manufacturing facility.

Suppliers⁷ 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;
• adding a raw material supplier;
• adding an alternate supplier for the UV chromophore for an intraocular lens;
• making a change in sterilization test site for sterilization test samples.

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 reffered to as the annual report). 21 CFR 814.39(b).

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.

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;
• eliminating certain in-process or final device tests, to eliminate test redundancy, waste, or use test samples selected during processing more efficiently;
• changing sample size in a bacterial endotoxin test assay;
• removing a rejection criterion for component acceptance in an in-process inspection step;
• adding inspection steps in direct response to field failures of the device.

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 guidance entitled, Modifications to Devices Subject to Premarket Approval (PMA) – The PMA Supplement Decision-Making Process.⁸

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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, a 75-day HDE supplement, or another alternate submission, e.g., real-time supplement, as appropriate.

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.¹⁰ 21 CFR 814.39(b), 814.126(b)(1).

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. 12 CFR 814.39(a).

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• a description of the change (any illustrative pictures should also be included);
• a summary of the data or information supporting the change, e.g., a few concise pages summarizing the key results; and
• a statement that the change has been made under the requirements of § 520(f) of the FDCA and 21 CFR. Part 820.

A 30-day notice should also contain:

• a description of the device;
• identification of the manufacturing facilities where the change will be implemented;
• reason for the change, including a description of any adverse events or field failures that have occurred;
• appendices of supporting data, where appropriate.

The summary of the data or information supporting the change, should include:

• a summary of the procedures established for the identification, documentation, validation, review, and approval of the manufacturing changes submitted in the 30-day notice;
• the statistical rationale for the sampling method, if you plan to verify the changed processes by routine sampling and independent measurement;
• a description of how you will monitor and control any manufacturing process you intend to change;
• a summary of the completed validation study that demonstrates that the manufacturing change can be made without significantly changing the operation of the final device. This summary should be 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. See 21 CFR 814.39(a)(3).

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http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/ PremarketSubmissions/PremarketApprovalPMA/ucm048161.htm