january 19, 2016 food and drug administration 5630 fishers ......supplement for a site change is...

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January 19, 2016

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

Re: Docket No. FDA-2015-N-3454: “Manufacturing Site Change Supplements:

Content and Submission; Draft Guidance for Industry and Food and Drug

Administration Staff.”

Dear Sir or Madam:

The Advanced Medical Technology Association (“AdvaMed”) is pleased to provide

comments on FDA’s draft guidance “Manufacturing Site Change Supplements: Content and

Submission; Draft Guidance for Industry and Food and Drug Administration Staff.”

AdvaMed represents manufacturers of medical devices, diagnostic products, and health

information systems that are transforming health care through earlier disease detection, less

invasive procedures, and more effective treatment. Our members range from the smallest to

the largest medical technology innovators.

We welcome this draft guidance and note that it helps to clarify the appropriate pathway for

these types of manufacturing changes. Our general and specific comments are provided in

the attached.

Respectfully submitted,

/s/

Sharon A. Segal, Ph.D.

Vice President

Technology and Regulatory Affairs

Attachment

ADVAMED COMMENTS “Manufacturing Site Change Supplements: Content and Submission; Draft Guidance for Industry and Food and Drug Administration Staff”

Line(s) No. – Line or lines numbers of the guidance Change – Proposed change to the guidance Reason – Reason/rationale for proposed change

# Line(s) No. Change Reason

1. Throughout document

Define – “manufactured” vs. “assembled” vs. “processed” This terminology is used throughout, and the scope of all of these activities is unclear.

2. General Provide additional explanation for which activities would constitute “finished device manufacturing” vs. “component manufacturing,” and incorporate risk assessment.

Guidance seems to be delineating risk level and appropriate submission type based solely on whether activities are performed on a finished device or on a component. What is the distinction between a finished device sub-process and component process, and how is risk considered? Example 1.a., under the heading for changes to a finished device, applies to a component. Clarification is needed.

3. General Incorporate determination of whether or not a process is critical to decision-making process.

Criticality is only mentioned with respect to components. There is no mention of whether or not a process is critical and how this would impact submission type.

4. General Provide additional examples of different device types within each of the 7 categories listed in Table 1. Provide more specific examples and more variety, including IVD examples.

Explanation and clarity. For example, moving a piece of equipment entails a different level of risk than moving a line.

5. 112-115, 137-140

Please provide further guidance on the types of manufacturing site changes that would not affect the safety and effectiveness of the device. These changes could be reported to FDA in the PMA periodic report or 30-Day Notice.

The guidance states on lines 112-115, “This draft 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.” However, the only guidance on when you should submit a PMA supplement for a site change is found in lines 137-140, “…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.”

No specific guidance is given for manufacturing site changes that may be implemented without a PMA supplement. Provide some examples of possible cases that might not affect safety and effectiveness. For example, contract manufacturing site



changes for low-risk accessories approved under a PMA may not affect the safety or effectiveness of a device.

6. 212-214

Revise as follows:

“change the site used to manufacture, process, or package manufacturing site (including a change to the processing, packaging, or sterilization site) of your legally marketed PMA-approved device.”

21 CFR 814.39(a)(3) includes sites used to “manufacture, process, or package” a device and doesn’t include the term “sterilization.” Sterilization is presumed to be a process applied to a device, and a sterilization site would be within the category of sites used to process a device.

7. 219-221

Revise as follows:

“This guidance does not address manufacturing site changes for devices cleared under premarket notification (510(k)) submissions or currently under an IDE.”

Important to note that devices under an IDE are also out of scope.

8. 232

(Definitions) Delete footnote 14 and ensure that all definitions align with statutory or regulatory definitions.

Footnote 14 indicates that, unless otherwise specified, the defined terms in this guidance are only for the purpose of this guidance. Where definitions already exist in statutes or in FDA-promulgated regulations, the definition in this guidance should align with those already formulated definitions.

9. 232

(Definitions)

Add a definition for “Site” and “relocation site.” Note that relocation should be clarified to show that it could be an expansion site.

Table 1 uses the terms “site” and “relocation site,” which are not defined in this section, in addition to “facility” and “establishment,” which are defined. It is not clear if “site” refers to the manufacturer only or to the location of the facility.

10. 248-251 Provide clarification whether an Establishment has a single FEI. Clarification.



11. 259-260

Revise as follows:

“Manufacturing Site: A facility or establishment used to manufacture, process, or package a finished device or accessory of any finished device.

Note: A facility that manufacturers only a component of a finished device is not considered a manufacturing site.”

The definition of “Finished Device” already includes “accessory to any device.”

Although clarified later in the document that 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, inclusion of this note at the beginning of the document when the definition is introduced will enhance understanding and application of the guidance document.

12. 276-294 Add a footnote citing to 21 CFR § 814.39 (e)(1). This part of the regulations allows for FDA to declare something from this list of PMA changes to be designated as a different submission type.

13. 278-279

Revise as follows:

“…PMA,. unless The only exception to this is if the change is a modification to the manufacturing procedure or method of . . .”

Editorial change to clarify a run-on sentence.

14. 338-339 Clarify “any original PMA”

Does FDA intend that “any original PMA” includes a PMA from the same manufacturer, but potentially a different PMA from the subject device?

Does FDA intend that “any original PMA” includes PMAs from other manufacturers? Some contract manufacturers may be approved manufacturing sites for PMAs for multiple manufacturers for similar devices.



15.

339; 358; Table 1-items 1, 2, 3a, 3b,6,

7a,7b, 7c; 391; 411; 423; 431; 457; 470; 478; 489; 550; 554;

590; 591; 596 (2 times); 651

Change “PMA” to: “PMA or PMA Supplement” throughout.

In the course of a device’s lifetime, manufacturing sites may change multiple times. One site may be approved in the original PMA, and a second site may be approved in a Site Change Supplement or a 180-Day PMA Supplement (which could incorporate design, manufacturing process, and site changes). Manufacturing sites approved via PMA supplements are also approved manufacturing sites.

16.

341; 342; 359; 360; 361; 362;

Table 1-items 1a, 3a; 395;

424; 617

Many places in the document refer to similar devices and similar processes. FDA should clarify what they mean by “similar.”

“Similar” is a highly subjective/qualitative term.

17. 344 Define “device type” in Footnote 18.

In footnote 18 referenced in line 344, the draft guidance states ‘….FDA to consider both the site’s familiarity with the manufacturing technology and the device type of the device manufactured at the site.’

Further, use of “device type” is confusing as Table 1 refers to ‘”the same or a similar Class II or Class III device” in the determination of the type of supplements required.

18. 353

Provide more clarity as to whether or not “related changes to the method of manufacture” within a 180-Day supplement can be included or must be referenced as part of a separate, connected, 30-Day Notice.

One branch at FDA recently provided feedback on site-change supplements, stating that if manufacturing process changes are required as a result of a site move, the manufacturing changes must be submitted as part of a separate 30-Day Notice referenced within the 180-Day supplement. This statement in the guidance suggests that related process changes may be included in a manufacturing site change supplement.



19. 358-359 Clarify “already approved in a PMA”

Does FDA intend that “any original PMA” includes a PMA from the same manufacturer, but potentially a different PMA from the subject device?

Does FDA intend that “any original PMA” includes PMAs from other manufacturers? Some contract manufacturers may be approved manufacturing sites for PMAs from multiple manufacturers for similar devices.

20. 360

Revise as follows:

“. . . manufacturing activities and for the same or similar Class II or Class III device as those as the PMA approved site.”

For consistency with other parts of the document.

21. 378

Add to Table 1: Moving (or expanding) the components operations for a finished device to a different facility or a different establishment would require a 30-day Notice.

Provide an example in the text that follows the table.

Also, Insert new sentence at end of paragraph:

“Components are also manufactured in-house (in a facility owned and operated by the PMA-holder). If the manufacturer wishes to change the facility where the component is manufactured and the component is critical to the finished device’s function, operation or specification, then the manufacturer should submit a 30-day notice under 21 CFR § 814.39(f). If the component is not critical, then changing the site may be reported in the PMA periodic report.”

To clarify that the same decision-making process applies to components manufactured in-house as to those manufactured by an external supplier.

22. Table 1 Add discussion of moves within the same clean room to Table 1.

FDA has provided inconsistent guidance regarding these moves. Sometimes FDA asks to include in Periodic Reports and other times to submit though 30-day notice. More clarification is needed.

23. 385 Spellcheck for typographical; “form” when it should be “from” (this occurs in Table 1-1 and throughout)

Editorial – correct typographical error.



24. 385 In Table 1 (specifically points 1(a) and 3(a)) the draft guidance refers to “the same or a similar Class II or Class III device.”

It would be helpful if the document included some examples of what FDA considers “the same or a similar Class II or Class III device” to ensure correct interpretation.

25. 385 Add definition for supplier and contract manufacturer, and use these terms consistently in the document.

In Table 1, (specifically points 7(a)-(c)) the draft guidance refers to “contract manufacturer” for components, but the document refers frequently to “suppliers.”

26. Table 1, Item

1b

Revise as follows:

“If the moved activities involve critical processes and are not already conducted at the relocation site”

Depending on the type and criticality of the process, these activities may be applicable for a 30-day notice or may not affect safety and effectiveness and could be included in the annual report.

27. Table 1, Item

3b

Revise as follows:

“In-house from a contract manufacturer included in the original PMA for activities that involve critical processes and are not already conducted in-house for a different class II or class III finished device.”

Depending on the type and criticality of the process, these activities may be applicable for a 30-Day Notice or may not affect safety and effectiveness and could be included in the annual report.

28. Table 1, item

5

Revise as follows:

“Expanding Moving manufacturing, processing, or packaging activities for a finished device into a building nearby . . .”

Also, explain in the text that the concepts apply to both moves and expansions.

Consistency. The other examples use the term “Moving,” not expanding and it is not clear why “Expanding” was used here.

29. Table 1, Item 5 and 448-

454

Change to indicate that a 30-day notice is sufficient for moving manufacturing to a nearby building provided that the building shares the same quality system, expertise in the processes to be conducted, and a similar inspectional compliance history as the existing site.

It seems arbitrary that a change from one part of a building to another part of a building only necessitates a 30-day notice and a change from one building to another nearby building (with a different FEI) requires a site change notification providing that the nearby building is covered by the same quality system, expertise in the processes to be conducted, and a similar inspectional compliance history.



30. Table 1, Item

6

Revise as follows:

“Moving the manufacturing, processing, or packaging activities for a finished device to a contract manufacturer not approved as part of the original PMA or submitted as a PMA supplement or 30-Day Notice and the change could affect the safety and effectiveness of the device.”

Changes could have been submitted to FDA as a PMA supplement or 30-Day Notice. Depending on the type and criticality of the process, these activities may be applicable for a 30-Day Notice or may not affect safety and effectiveness and could be included in the annual report.

31.

Table 1, Items 7a, 7b,

and 7c

Remove sub-bullets to number 7. Per table, all component moves qualify for 30-day notice.

32. Table 1, Item

7 Provide additional examples that do not involve movement between device manufacturer and contract manufacturer

Explanation and clarity.

33. 401

Add the following example or a similar example to #1 (e.g., this would be example 1.b.) to address what is meant by “or other class II or class III device.”

Does “or other class II or class III device” mean the company’s other class II or class III device, or a different company’s class II or class III device. Clarity is needed.

Similar to comment on line 385.

34. 443-446

Revise as follows:

“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 first floor to the third floor of the currently-approved establishment facility. A 30-Day Notice should be submitted.”

Changing the example to be from an intra-building change to an inter-building change reduces confusion. The guidance states that this is an example of moving “from one facility to another within the same establishment” (see lines 440-441), but the example describes moving from the first floor to the third floor of, presumably, the same building. This is confusing, because the guidance defines “facility” as “the physical structures or buildings within an establishment.” This definition does not apply to a within-building move.



35. 459 Replace the example with an example that is clearer and more representative of the change.

This example seems more applicable to 7(b), which is the manufacturing move of a component to a contract manufacturer not approved as part of the original PMA, which requires a 30-Day Notice.

Can the example in line 459 be replaced with a manufacturing move of a finished device that requires a Site Change Supplement?

36. 459-464

Delete example and replace with the following:

“For example ABC, an applicant, is the PMA holder of a cardiac pacemaker system. The PMA was approved for ABC to clean and test the pacemaker as well as to package and label the system. The manufacturing of the pacemaker is performed by the contract manufacturer XYZ, Inc. ABC plans to move the manufacturing of the pacemaker to another contract manufacturer that was not part of the original PMA. A site change supplement should be submitted.”

The stent should be considered a critical component and not a finished device. The stent is not separately distributed and is not capable of functioning without the stent delivery system (especially self-expanding stents). Stent manufacturing location changes should qualify for 30-Day Notice.

37. 502 –

Footnote 10

Revise as follows (add to the end of the footnote):

“Including the change in the PMA Annual Report would be appropriate.”

Define what to do with changes that are not subject to submission.

38. 513, 517 Delete “distribution” from the list of information to be included in a site change supplement.

Distribution sites are not within the scope of the guidance unless the sites also perform manufacturing, processing, or packaging activities.

39. 538-539

Revise as follows:

“Accordingly, you should provide an expected date when the facility will be ready for inspection list the planned completion dates for any processes that have not been validated at the time of the submission of the PMA supplement.”

This is the language suggested in FDA’s template for Original PMA Cover Letters (link to FDA website). Providing one date for inspectional readiness is less burdensome than providing multiple completion dates for multiple processes.

40. 541-544 Provide clarification about how manufacturers should decide when and when not to provide process validation reports.

The guidance says that process validation reports need not be provided when FDA will conduct an inspection with a site change supplement. More guidance should be given on how (and when) manufacturers can get a final decision on when an inspection will be required.

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm050289.htm



41. 647

Revise as follows:

Insert at end of paragraph: “Manufacturers can obtain feedback from FDA on whether an inspection will likely be required by utilizing the FDA’s Pre-Submission Program.”

Knowing in advance whether an inspection will be required for a manufacturing site change will allow manufacturers to better predict timelines associated with the FDA review cycle. See also comment on Lines 541-544 above.

42. 650, Table 2

In Table 2 (or perhaps a flowchart), explain how the “risk to the safety or effectiveness of the device associated with the manufacturing activities at the new site” (as stated in lines 620-621) plays into FDA’s decision on whether an inspection will be required.

Table 2 does not address how risk to safety or effectiveness of the device will weigh in FDA’s decision on whether to require an inspection with a manufacturing site change supplement.

43. 650, Table 2 Replace Table 2 with a flowchart such as below:

The table is more complicated than necessary. A flow-chart will be more effective at communicating the same information.



44. 653 Add a section describing expected timelines for scheduling and completing inspections.

This information would be helpful for manufacturers to maintain supply continuity.



45. 488

Revise as follows:

“c. Moving component manufacturing of a critical component in-house from a contract manufacturer included in the original PMA:”

For example, ABC, an applicant, uses contract manufacturer XYZ to manufacture the balloon used in its cardiac stent device. ABC would now like to manufacture the balloon in-house. A 30-Day Notice should be submitted because that component is considered critical and the modification affects the device’s safety or effectiveness.”

The example identifies the component as a critical component. Include this element in the introductory sentence.

january 19, 2016 food and drug administration 5630 fishers ......supplement for a site change is...

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