701 Pennsylvania Avenue, Ste. 800
Washington, DC 20004–2654
Tel: 202 783 8700
Fax: 202 783 8750
www.AdvaMed.org
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Content and Submission; Draft Guidance for Industry and Food and Drug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comments on FDA’s draft guidance “Manufacturing Site Change Supplements: Content and
Submission; Draft Guidance for Industry and Food and Drug Administration Staff.”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We welcome this draft guidance and note that it helps to clarify the appropriate pathway for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Draft Guidance for Industry and Food and Drug Administration Staff”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
#
1.
Line(s) No.
Change
Reason
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
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
Change
Reason
changes for low-risk accessories approved under a PMA may
not affect the safety or effectiveness of a device.
Revise as follows:
6.
212-214
“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 PMAapproved 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.
Revise as follows:
7.
8.
9.
10.
219-221
232
(Definitions)
232
(Definitions)
248-251
“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.
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 FDApromulgated regulations, the definition in this guidance should
align with those already formulated 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.
Provide clarification whether an Establishment has a single FEI.
Clarification.
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
11.
259-260
Change
Reason
Revise as follows:
The definition of “Finished Device” already includes “accessory
to any device.”
“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.”
12.
276-294
13.
278-279
Add a footnote citing to 21 CFR § 814.39 (e)(1).
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.
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.
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.
Does FDA intend that “any original PMA” includes a PMA from
the same manufacturer, but potentially a different PMA from the
subject device?
14.
338-339
Clarify “any original PMA”
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.
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
339; 358;
Table 1-items
1, 2, 3a, 3b,6,
7a,7b, 7c;
391; 411;
15.
423; 431;
457; 470;
478; 489;
550; 554;
590; 591; 596
(2 times); 651
341; 342;
359; 360;
361; 362;
16.
Table 1-items
1a, 3a; 395;
424; 617
17.
344
Change
Change “PMA” to: “PMA or PMA Supplement” throughout.
Many places in the document refer to similar devices and similar
processes. FDA should clarify what they mean by “similar.”
Define “device type” in Footnote 18.
Reason
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.
“Similar” is a highly subjective/qualitative term.
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.
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
Change
Reason
Does FDA intend that “any original PMA” includes a PMA from
the same manufacturer, but potentially a different PMA from the
subject device?
19.
358-359
20.
360
Clarify “already approved in a PMA”
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.
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.
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:
21.
378
22.
Table 1
23.
385
“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.
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.
Spellcheck for typographical; “form” when it should be “from”
(this occurs in Table 1-1 and throughout)
Editorial – correct typographical error.
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
Change
Reason
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”
Revise as follows:
27.
Table 1, Item
3b
“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.
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.
Revise as follows:
28.
Table 1, item
5
“Expanding Moving manufacturing, processing, or packaging
activities for a finished device into a building nearby . . .”
Consistency. The other examples use the term “Moving,” not
expanding and it is not clear why “Expanding” was used here.
Also, explain in the text that the concepts apply to both moves
and expansions.
29.
Table 1, Item
5 and 448454
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.
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
Change
Revise as follows:
30.
31.
32.
33.
Table 1, Item
6
“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.”
Reason
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.
Table 1,
Items 7a, 7b,
and 7c
Remove sub-bullets to number 7.
Per table, all component moves qualify for 30-day notice.
Table 1, Item
7
Provide additional examples that do not involve movement
between device manufacturer and contract manufacturer
Explanation and clarity.
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.
Revise as follows:
34.
443-446
“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.
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
35.
459
Change
Replace the example with an example that is clearer and more
representative of the change.
Reason
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 30Day Notice.
Can the example in line 459 be replaced with a manufacturing
move of a finished device that requires a Site Change
Supplement?
Delete example and replace with the following:
36.
459-464
37.
502 –
Footnote 10
38.
513, 517
“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.”
Revise as follows (add to the end of the footnote):
“Including the change in the PMA Annual Report would be
appropriate.”
Delete “distribution” from the list of information to be included in
a site change supplement.
Revise as follows:
39.
40.
538-539
541-544
“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.”
Provide clarification about how manufacturers should decide
when and when not to provide process validation reports.
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.
Define what to do with changes that are not subject to
submission.
Distribution sites are not within the scope of the guidance unless
the sites also perform manufacturing, processing, or packaging
activities.
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.
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.
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
41.
647
42.
650, Table 2
43.
650, Table 2
Change
Reason
Revise as follows:
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.
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.”
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 620621) plays into FDA’s decision on whether an inspection will be
required.
Replace Table 2 with a flowchart such as below:
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.
The table is more complicated than necessary. A flow-chart will
be more effective at communicating the same information.
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
44.
653
Change
Reason
Add a section describing expected timelines for scheduling and
completing inspections.
This information would be helpful for manufacturers to maintain
supply continuity.
ADVAMED COMMENTS
“Manufacturing Site Change Supplements: Content and Submission;
Draft Guidance for Industry and Food and Drug Administration Staff”
#
Line(s) No.
Change
Reason
Revise as follows:
“c. Moving component manufacturing of a critical component
in-house from a contract manufacturer included in the original
PMA:”
45.
488
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 30Day 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.