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2025-08-15T11:45:05-04:00
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Food
F
o
o
d
and
a
n
d
Drug
D
r
u
g
Administration,
A
d
m
i
n
i
s
t
r
a
t
i
o
n
,
HHS
H
H
S
Pt.
P
t
.
4
4
jspears
j
s
p
e
a
r
s
on
o
n
DSK121TN23PROD
D
S
K
1
2
1
T
N
2
3
P
R
O
D
with
w
i
t
h
CFR
C
F
R
and
a
n
d
any
a
n
y
consulting
c
o
n
s
u
l
t
i
n
g
agency
a
g
e
n
c
y
compo-
c
o
m
p
o
-
nents.
n
e
n
t
s
.
The
T
h
e
product
p
r
o
d
u
c
t
jurisdiction
j
u
r
i
s
d
i
c
t
i
o
n
officer
o
f
f
i
c
e
r
may
m
a
y
request
r
e
q
u
e
s
t
a
a
meeting
m
e
e
t
i
n
g
with
w
i
t
h
the
t
h
e
spon-
s
p
o
n
-
sor
s
o
r
during
d
u
r
i
n
g
the
t
h
e
review
r
e
v
i
e
w
period
p
e
r
i
o
d
to
t
o
discuss
d
i
s
c
u
s
s
the
t
h
e
request
r
e
q
u
e
s
t
for
f
o
r
designation.
d
e
s
i
g
n
a
t
i
o
n
.
If
I
f
the
t
h
e
prod-
p
r
o
d
-
uct
u
c
t
jurisdiction
j
u
r
i
s
d
i
c
t
i
o
n
officer
o
f
f
i
c
e
r
has
h
a
s
not
n
o
t
issued
i
s
s
u
e
d
a
a
letter
l
e
t
t
e
r
of
o
f
designation
d
e
s
i
g
n
a
t
i
o
n
within
w
i
t
h
i
n
60
6
0
days
d
a
y
s
of
o
f
the
t
h
e
filing
f
i
l
i
n
g
date
d
a
t
e
of
o
f
a
a
request
r
e
q
u
e
s
t
for
f
o
r
designa-
d
e
s
i
g
n
a
-
tion,
t
i
o
n
,
the
t
h
e
sponsor’s
s
p
o
n
s
o
r
’
s
recommendation
r
e
c
o
m
m
e
n
d
a
t
i
o
n
of
o
f
the
t
h
e
center
c
e
n
t
e
r
with
w
i
t
h
primary
p
r
i
m
a
r
y
jurisdiction,
j
u
r
i
s
d
i
c
t
i
o
n
,
in
i
n
accordance
a
c
c
o
r
d
a
n
c
e
with
w
i
t
h
§
§
3.7(c)(3),
3
.
7
(
c
)
(
3
)
,
shall
s
h
a
l
l
be-
b
e
-
come
c
o
m
e
the
t
h
e
designated
d
e
s
i
g
n
a
t
e
d
agency
a
g
e
n
c
y
compo-
c
o
m
p
o
-
nent.
n
e
n
t
.
(c)
(
c
)
Request
R
e
q
u
e
s
t
for
f
o
r
reconsideration
r
e
c
o
n
s
i
d
e
r
a
t
i
o
n
by
b
y
sponsor:
s
p
o
n
s
o
r
:
If
I
f
the
t
h
e
sponsor
s
p
o
n
s
o
r
disagrees
d
i
s
a
g
r
e
e
s
with
w
i
t
h
the
t
h
e
designation,
d
e
s
i
g
n
a
t
i
o
n
,
it
i
t
may
m
a
y
request
r
e
q
u
e
s
t
the
t
h
e
product
p
r
o
d
u
c
t
jurisdiction
j
u
r
i
s
d
i
c
t
i
o
n
officer
o
f
f
i
c
e
r
to
t
o
recon-
r
e
c
o
n
-
sider
s
i
d
e
r
the
t
h
e
decision
d
e
c
i
s
i
o
n
by
b
y
filing,
f
i
l
i
n
g
,
within
w
i
t
h
i
n
15
1
5
days
d
a
y
s
of
o
f
receipt
r
e
c
e
i
p
t
of
o
f
the
t
h
e
letter
l
e
t
t
e
r
of
o
f
designa-
d
e
s
i
g
n
a
-
tion,
t
i
o
n
,
a
a
written
w
r
i
t
t
e
n
request
r
e
q
u
e
s
t
for
f
o
r
reconsider-
r
e
c
o
n
s
i
d
e
r
-
ation
a
t
i
o
n
not
n
o
t
exceeding
e
x
c
e
e
d
i
n
g
5
5
pages.
p
a
g
e
s
.
No
N
o
new
n
e
w
in-
i
n
-
formation
f
o
r
m
a
t
i
o
n
may
m
a
y
be
b
e
included
i
n
c
l
u
d
e
d
in
i
n
a
a
request
r
e
q
u
e
s
t
for
f
o
r
reconsideration.
r
e
c
o
n
s
i
d
e
r
a
t
i
o
n
.
The
T
h
e
product
p
r
o
d
u
c
t
juris-
j
u
r
i
s
-
diction
d
i
c
t
i
o
n
officer
o
f
f
i
c
e
r
shall
s
h
a
l
l
review
r
e
v
i
e
w
and
a
n
d
act
a
c
t
on
o
n
the
t
h
e
request
r
e
q
u
e
s
t
in
i
n
writing
w
r
i
t
i
n
g
within
w
i
t
h
i
n
15
1
5
days
d
a
y
s
of
o
f
its
i
t
s
receipt.
r
e
c
e
i
p
t
.
§
§
3.9
3
.
9
Effect
E
f
f
e
c
t
of
o
f
letter
l
e
t
t
e
r
of
o
f
designation.
d
e
s
i
g
n
a
t
i
o
n
.
(a)
(
a
)
The
T
h
e
letter
l
e
t
t
e
r
of
o
f
designation
d
e
s
i
g
n
a
t
i
o
n
con-
c
o
n
-
stitutes
s
t
i
t
u
t
e
s
an
a
n
agency
a
g
e
n
c
y
determination
d
e
t
e
r
m
i
n
a
t
i
o
n
that
t
h
a
t
is
i
s
subject
s
u
b
j
e
c
t
to
t
o
change
c
h
a
n
g
e
only
o
n
l
y
as
a
s
provided
p
r
o
v
i
d
e
d
in
i
n
paragraph
p
a
r
a
g
r
a
p
h
(b)
(
b
)
of
o
f
this
t
h
i
s
section.
s
e
c
t
i
o
n
.
(b)
(
b
)
The
T
h
e
product
p
r
o
d
u
c
t
jurisdiction
j
u
r
i
s
d
i
c
t
i
o
n
officer
o
f
f
i
c
e
r
may
m
a
y
change
c
h
a
n
g
e
the
t
h
e
designated
d
e
s
i
g
n
a
t
e
d
agency
a
g
e
n
c
y
component
c
o
m
p
o
n
e
n
t
with
w
i
t
h
the
t
h
e
written
w
r
i
t
t
e
n
consent
c
o
n
s
e
n
t
of
o
f
the
t
h
e
sponsor,
s
p
o
n
s
o
r
,
or
o
r
without
w
i
t
h
o
u
t
its
i
t
s
consent
c
o
n
s
e
n
t
to
t
o
protect
p
r
o
t
e
c
t
the
t
h
e
public
p
u
b
l
i
c
health
h
e
a
l
t
h
or
o
r
for
f
o
r
other
o
t
h
e
r
compelling
c
o
m
p
e
l
l
i
n
g
reasons.
r
e
a
s
o
n
s
.
A
A
sponsor
s
p
o
n
s
o
r
shall
s
h
a
l
l
be
b
e
given
g
i
v
e
n
30
3
0
days
d
a
y
s
written
w
r
i
t
t
e
n
notice
n
o
t
i
c
e
of
o
f
any
a
n
y
pro-
p
r
o
-
posed
p
o
s
e
d
nonconsensual
n
o
n
c
o
n
s
e
n
s
u
a
l
change
c
h
a
n
g
e
in
i
n
des-
d
e
s
-
ignated
i
g
n
a
t
e
d
agency
a
g
e
n
c
y
component.
c
o
m
p
o
n
e
n
t
.
The
T
h
e
spon-
s
p
o
n
-
sor
s
o
r
may
m
a
y
request
r
e
q
u
e
s
t
an
a
n
additional
a
d
d
i
t
i
o
n
a
l
30
3
0
days
d
a
y
s
to
t
o
submit
s
u
b
m
i
t
written
w
r
i
t
t
e
n
objections,
o
b
j
e
c
t
i
o
n
s
,
not
n
o
t
to
t
o
ex-
e
x
-
ceed
c
e
e
d
15
1
5
pages,
p
a
g
e
s
,
to
t
o
the
t
h
e
proposed
p
r
o
p
o
s
e
d
change,
c
h
a
n
g
e
,
and
a
n
d
shall
s
h
a
l
l
be
b
e
granted,
g
r
a
n
t
e
d
,
upon
u
p
o
n
request,
r
e
q
u
e
s
t
,
a
a
timely
t
i
m
e
l
y
meeting
m
e
e
t
i
n
g
with
w
i
t
h
the
t
h
e
product
p
r
o
d
u
c
t
juris-
j
u
r
i
s
-
diction
d
i
c
t
i
o
n
officer
o
f
f
i
c
e
r
and
a
n
d
appropriate
a
p
p
r
o
p
r
i
a
t
e
center
c
e
n
t
e
r
officials.
o
f
f
i
c
i
a
l
s
.
Within
W
i
t
h
i
n
30
3
0
days
d
a
y
s
of
o
f
receipt
r
e
c
e
i
p
t
of
o
f
the
t
h
e
sponsor’s
s
p
o
n
s
o
r
’
s
written
w
r
i
t
t
e
n
objections,
o
b
j
e
c
t
i
o
n
s
,
the
t
h
e
product
p
r
o
d
u
c
t
jurisdiction
j
u
r
i
s
d
i
c
t
i
o
n
officer
o
f
f
i
c
e
r
shall
s
h
a
l
l
issue
i
s
s
u
e
to
t
o
the
t
h
e
sponsor,
s
p
o
n
s
o
r
,
with
w
i
t
h
copies
c
o
p
i
e
s
to
t
o
appro-
a
p
p
r
o
-
priate
p
r
i
a
t
e
center
c
e
n
t
e
r
officials,
o
f
f
i
c
i
a
l
s
,
a
a
written
w
r
i
t
t
e
n
deter-
d
e
t
e
r
-
mination
m
i
n
a
t
i
o
n
setting
s
e
t
t
i
n
g
forth
f
o
r
t
h
a
a
statement
s
t
a
t
e
m
e
n
t
of
o
f
reasons
r
e
a
s
o
n
s
for
f
o
r
the
t
h
e
proposed
p
r
o
p
o
s
e
d
change
c
h
a
n
g
e
in
i
n
des-
d
e
s
-
ignated
i
g
n
a
t
e
d
agency
a
g
e
n
c
y
component.
c
o
m
p
o
n
e
n
t
.
A
A
non-
n
o
n
-
consensual
c
o
n
s
e
n
s
u
a
l
change
c
h
a
n
g
e
in
i
n
the
t
h
e
designated
d
e
s
i
g
n
a
t
e
d
agency
a
g
e
n
c
y
component
c
o
m
p
o
n
e
n
t
requires
r
e
q
u
i
r
e
s
the
t
h
e
concur-
c
o
n
c
u
r
-
177
1
7
7
rence
r
e
n
c
e
of
o
f
the
t
h
e
Principal
P
r
i
n
c
i
p
a
l
Associate
A
s
s
o
c
i
a
t
e
Com-
C
o
m
-
missioner.
m
i
s
s
i
o
n
e
r
.
[56
[
5
6
FR
F
R
58756,
5
8
7
5
6
,
Nov.
N
o
v
.
21,
2
1
,
1991,
1
9
9
1
,
as
a
s
amended
a
m
e
n
d
e
d
at
a
t
68
6
8
FR
F
R
37077,
3
7
0
7
7
,
June
J
u
n
e
23,
2
3
,
2003]
2
0
0
3
]
§
§
3.10
3
.
1
0
Stay
S
t
a
y
of
o
f
review
r
e
v
i
e
w
time.
t
i
m
e
.
Any
A
n
y
filing
f
i
l
i
n
g
with
w
i
t
h
or
o
r
review
r
e
v
i
e
w
by
b
y
the
t
h
e
product
p
r
o
d
u
c
t
jurisdiction
j
u
r
i
s
d
i
c
t
i
o
n
officer
o
f
f
i
c
e
r
stays
s
t
a
y
s
the
t
h
e
review
r
e
v
i
e
w
clock
c
l
o
c
k
or
o
r
other
o
t
h
e
r
established
e
s
t
a
b
l
i
s
h
e
d
time
t
i
m
e
periods
p
e
r
i
o
d
s
for
f
o
r
agency
a
g
e
n
c
y
action
a
c
t
i
o
n
for
f
o
r
an
a
n
appli-
a
p
p
l
i
-
cation
c
a
t
i
o
n
for
f
o
r
marketing
m
a
r
k
e
t
i
n
g
approval
a
p
p
r
o
v
a
l
or
o
r
re-
r
e
-
quired
q
u
i
r
e
d
investigational
i
n
v
e
s
t
i
g
a
t
i
o
n
a
l
notice
n
o
t
i
c
e
during
d
u
r
i
n
g
the
t
h
e
pendency
p
e
n
d
e
n
c
y
of
o
f
the
t
h
e
review
r
e
v
i
e
w
by
b
y
the
t
h
e
prod-
p
r
o
d
-
uct
u
c
t
jurisdiction
j
u
r
i
s
d
i
c
t
i
o
n
officer.
o
f
f
i
c
e
r
.
Subpart
S
u
b
p
a
r
t
B
B
[Reserved]
[
R
e
s
e
r
v
e
d
]
PART
P
A
R
T
4—REGULATION
4
—
R
E
G
U
L
A
T
I
O
N
OF
O
F
COMBINATION
C
O
M
B
I
N
A
T
I
O
N
PRODUCTS
P
R
O
D
U
C
T
S
Subpart
S
u
b
p
a
r
t
A—Current
A
—
C
u
r
r
e
n
t
Good
G
o
o
d
Manufacturing
M
a
n
u
f
a
c
t
u
r
i
n
g
Practice
P
r
a
c
t
i
c
e
Requirements
R
e
q
u
i
r
e
m
e
n
t
s
for
f
o
r
Combina-
C
o
m
b
i
n
a
-
tion
t
i
o
n
Products
P
r
o
d
u
c
t
s
Sec.
S
e
c
.
4.1
4
.
1
What
W
h
a
t
is
i
s
the
t
h
e
scope
s
c
o
p
e
of
o
f
this
t
h
i
s
subpart?
s
u
b
p
a
r
t
?
4.2
4
.
2
How
H
o
w
does
d
o
e
s
FDA
F
D
A
define
d
e
f
i
n
e
key
k
e
y
terms
t
e
r
m
s
and
a
n
d
phrases
p
h
r
a
s
e
s
in
i
n
this
t
h
i
s
subpart?
s
u
b
p
a
r
t
?
4.3
4
.
3
What
W
h
a
t
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
prac-
p
r
a
c
-
tice
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
apply
a
p
p
l
y
to
t
o
my
m
y
combina-
c
o
m
b
i
n
a
-
tion
t
i
o
n
product?
p
r
o
d
u
c
t
?
4.4
4
.
4
How
H
o
w
can
c
a
n
I
I
comply
c
o
m
p
l
y
with
w
i
t
h
these
t
h
e
s
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
require-
r
e
q
u
i
r
e
-
ments
m
e
n
t
s
for
f
o
r
a
a
co-packaged
c
o
-
p
a
c
k
a
g
e
d
or
o
r
single-entity
s
i
n
g
l
e
-
e
n
t
i
t
y
combination
c
o
m
b
i
n
a
t
i
o
n
product?
p
r
o
d
u
c
t
?
Subpart
S
u
b
p
a
r
t
B—Postmarketing
B
—
P
o
s
t
m
a
r
k
e
t
i
n
g
Safety
S
a
f
e
t
y
Reporting
R
e
p
o
r
t
i
n
g
for
f
o
r
Combination
C
o
m
b
i
n
a
t
i
o
n
Products
P
r
o
d
u
c
t
s
4.100
4
.
1
0
0
What
W
h
a
t
is
i
s
the
t
h
e
scope
s
c
o
p
e
of
o
f
this
t
h
i
s
subpart?
s
u
b
p
a
r
t
?
4.101
4
.
1
0
1
How
H
o
w
does
d
o
e
s
FDA
F
D
A
define
d
e
f
i
n
e
key
k
e
y
terms
t
e
r
m
s
and
a
n
d
phrases
p
h
r
a
s
e
s
in
i
n
this
t
h
i
s
subpart?
s
u
b
p
a
r
t
?
4.102
4
.
1
0
2
What
W
h
a
t
reports
r
e
p
o
r
t
s
must
m
u
s
t
you
y
o
u
submit
s
u
b
m
i
t
to
t
o
FDA
F
D
A
for
f
o
r
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
or
o
r
con-
c
o
n
-
stituent
s
t
i
t
u
e
n
t
part?
p
a
r
t
?
4.103
4
.
1
0
3
What
W
h
a
t
information
i
n
f
o
r
m
a
t
i
o
n
must
m
u
s
t
you
y
o
u
share
s
h
a
r
e
with
w
i
t
h
other
o
t
h
e
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
applicants
a
p
p
l
i
c
a
n
t
s
for
f
o
r
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product?
p
r
o
d
u
c
t
?
4.104
4
.
1
0
4
How
H
o
w
and
a
n
d
where
w
h
e
r
e
must
m
u
s
t
you
y
o
u
submit
s
u
b
m
i
t
post-
p
o
s
t
-
marketing
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reports
r
e
p
o
r
t
s
for
f
o
r
your
y
o
u
r
com-
c
o
m
-
bination
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
or
o
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part?
p
a
r
t
?
4.105
4
.
1
0
5
What
W
h
a
t
are
a
r
e
the
t
h
e
postmarketing
p
o
s
t
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
re-
r
e
-
porting
p
o
r
t
i
n
g
recordkeeping
r
e
c
o
r
d
k
e
e
p
i
n
g
requirements
r
e
q
u
i
r
e
m
e
n
t
s
for
f
o
r
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
or
o
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part?
p
a
r
t
?
AUTHORITY:
A
U
T
H
O
R
I
T
Y
:
21
2
1
U.S.C.
U
.
S
.
C
.
321,
3
2
1
,
331,
3
3
1
,
351,
3
5
1
,
352,
3
5
2
,
353,
3
5
3
,
355,
3
5
5
,
360,
3
6
0
,
360b–360f,
3
6
0
b
–
3
6
0
f
,
360h–360j,
3
6
0
h
–
3
6
0
j
,
360l,
3
6
0
l
,
360hh–360ss,
3
6
0
h
h
–
3
6
0
s
s
,
360aaa–360bbb,
3
6
0
a
a
a
–
3
6
0
b
b
b
,
371(a),
3
7
1
(
a
)
,
372–374,
3
7
2
–
3
7
4
,
379e,
3
7
9
e
,
381,
3
8
1
,
383,
3
8
3
,
394;
3
9
4
;
42
4
2
U.S.C.
U
.
S
.
C
.
216,
2
1
6
,
262,
2
6
2
,
263a,
2
6
3
a
,
264,
2
6
4
,
271.
2
7
1
.
EFFECTIVE
E
F
F
E
C
T
I
V
E
DATE
D
A
T
E
NOTE:
N
O
T
E
:
Amendments
A
m
e
n
d
m
e
n
t
s
to
t
o
the
t
h
e
part
p
a
r
t
4
4
authority
a
u
t
h
o
r
i
t
y
citation
c
i
t
a
t
i
o
n
were
w
e
r
e
published
p
u
b
l
i
s
h
e
d
at
a
t
VerDate
V
e
r
D
a
t
e
Sep<11>2014
S
e
p
<
1
1
>
2
0
1
4
11:20
1
1
:
2
0
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J
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13,
1
3
,
2025
2
0
2
5
Jkt
J
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2
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5
0
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§
§
4.1
4
.
1
21
2
1
CFR
C
F
R
Ch.
C
h
.
I
I
(4–1–25
(
4
–
1
–
2
5
Edition)
E
d
i
t
i
o
n
)
jspears
j
s
p
e
a
r
s
on
o
n
DSK121TN23PROD
D
S
K
1
2
1
T
N
2
3
P
R
O
D
with
w
i
t
h
CFR
C
F
R
90
9
0
FR
F
R
51765,
5
1
7
6
5
,
June
J
u
n
e
18,
1
8
,
2024,
2
0
2
4
,
effective
e
f
f
e
c
t
i
v
e
Dec.
D
e
c
.
18,
1
8
,
2025.
2
0
2
5
.
SOURCE:
S
O
U
R
C
E
:
78
7
8
FR
F
R
4321,
4
3
2
1
,
Jan.
J
a
n
.
22,
2
2
,
2013,
2
0
1
3
,
unless
u
n
l
e
s
s
otherwise
o
t
h
e
r
w
i
s
e
noted.
n
o
t
e
d
.
Subpart
S
u
b
p
a
r
t
A—Current
A
—
C
u
r
r
e
n
t
Good
G
o
o
d
Manu-
M
a
n
u
-
facturing
f
a
c
t
u
r
i
n
g
Practice
P
r
a
c
t
i
c
e
Require-
R
e
q
u
i
r
e
-
ments
m
e
n
t
s
for
f
o
r
Combination
C
o
m
b
i
n
a
t
i
o
n
Prod-
P
r
o
d
-
ucts
u
c
t
s
§
§
4.1
4
.
1
What
W
h
a
t
is
i
s
the
t
h
e
scope
s
c
o
p
e
of
o
f
this
t
h
i
s
subpart?
s
u
b
p
a
r
t
?
This
T
h
i
s
subpart
s
u
b
p
a
r
t
applies
a
p
p
l
i
e
s
to
t
o
combination
c
o
m
b
i
n
a
t
i
o
n
products.
p
r
o
d
u
c
t
s
.
It
I
t
establishes
e
s
t
a
b
l
i
s
h
e
s
which
w
h
i
c
h
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
require-
r
e
q
u
i
r
e
-
ments
m
e
n
t
s
apply
a
p
p
l
y
to
t
o
these
t
h
e
s
e
products.
p
r
o
d
u
c
t
s
.
This
T
h
i
s
subpart
s
u
b
p
a
r
t
clarifies
c
l
a
r
i
f
i
e
s
the
t
h
e
application
a
p
p
l
i
c
a
t
i
o
n
of
o
f
cur-
c
u
r
-
rent
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
regu-
r
e
g
u
-
lations
l
a
t
i
o
n
s
to
t
o
combination
c
o
m
b
i
n
a
t
i
o
n
products,
p
r
o
d
u
c
t
s
,
and
a
n
d
provides
p
r
o
v
i
d
e
s
a
a
regulatory
r
e
g
u
l
a
t
o
r
y
framework
f
r
a
m
e
w
o
r
k
for
f
o
r
designing
d
e
s
i
g
n
i
n
g
and
a
n
d
implementing
i
m
p
l
e
m
e
n
t
i
n
g
the
t
h
e
cur-
c
u
r
-
rent
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
oper-
o
p
e
r
-
ating
a
t
i
n
g
system
s
y
s
t
e
m
at
a
t
facilities
f
a
c
i
l
i
t
i
e
s
that
t
h
a
t
manu-
m
a
n
u
-
facture
f
a
c
t
u
r
e
co-packaged
c
o
-
p
a
c
k
a
g
e
d
or
o
r
single-entity
s
i
n
g
l
e
-
e
n
t
i
t
y
combination
c
o
m
b
i
n
a
t
i
o
n
products.
p
r
o
d
u
c
t
s
.
§
§
4.2
4
.
2
How
H
o
w
does
d
o
e
s
FDA
F
D
A
define
d
e
f
i
n
e
key
k
e
y
terms
t
e
r
m
s
and
a
n
d
phrases
p
h
r
a
s
e
s
in
i
n
this
t
h
i
s
subpart?
s
u
b
p
a
r
t
?
The
T
h
e
terms
t
e
r
m
s
listed
l
i
s
t
e
d
in
i
n
this
t
h
i
s
section
s
e
c
t
i
o
n
have
h
a
v
e
the
t
h
e
following
f
o
l
l
o
w
i
n
g
meanings
m
e
a
n
i
n
g
s
for
f
o
r
purposes
p
u
r
p
o
s
e
s
of
o
f
this
t
h
i
s
subpart:
s
u
b
p
a
r
t
:
Biological
B
i
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
set
s
e
t
forth
f
o
r
t
h
in
i
n
§
§
3.2(d)
3
.
2
(
d
)
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
A
A
bio-
b
i
o
-
logical
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
also
a
l
s
o
meets
m
e
e
t
s
the
t
h
e
defini-
d
e
f
i
n
i
-
tions
t
i
o
n
s
of
o
f
either
e
i
t
h
e
r
a
a
drug
d
r
u
g
or
o
r
device
d
e
v
i
c
e
as
a
s
these
t
h
e
s
e
terms
t
e
r
m
s
are
a
r
e
defined
d
e
f
i
n
e
d
under
u
n
d
e
r
this
t
h
i
s
section.
s
e
c
t
i
o
n
.
Combination
C
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
set
s
e
t
forth
f
o
r
t
h
in
i
n
§
§
3.2(e)
3
.
2
(
e
)
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Constituent
C
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
is
i
s
a
a
drug,
d
r
u
g
,
device,
d
e
v
i
c
e
,
or
o
r
biological
b
i
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
that
t
h
a
t
is
i
s
part
p
a
r
t
of
o
f
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product.
p
r
o
d
u
c
t
.
Co-packaged
C
o
-
p
a
c
k
a
g
e
d
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
set
s
e
t
forth
f
o
r
t
h
in
i
n
§
§
3.2(e)(2)
3
.
2
(
e
)
(
2
)
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Current
C
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
means
m
e
a
n
s
the
t
h
e
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
within
w
i
t
h
i
n
an
a
n
establishment
e
s
t
a
b
l
i
s
h
m
e
n
t
that
t
h
a
t
is
i
s
designed
d
e
s
i
g
n
e
d
and
a
n
d
implemented
i
m
p
l
e
m
e
n
t
e
d
to
t
o
address
a
d
d
r
e
s
s
and
a
n
d
meet
m
e
e
t
the
t
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufac-
m
a
n
u
f
a
c
-
turing
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
for
f
o
r
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product.
p
r
o
d
u
c
t
.
Current
C
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
means
m
e
a
n
s
the
t
h
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
set
s
e
t
forth
f
o
r
t
h
under
u
n
d
e
r
§
§
4.3(a)
4
.
3
(
a
)
through
t
h
r
o
u
g
h
(d).
(
d
)
.
Device
D
e
v
i
c
e
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
set
s
e
t
forth
f
o
r
t
h
in§
i
n
§
3.2(f)
3
.
2
(
f
)
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
A
A
device
d
e
v
i
c
e
that
t
h
a
t
is
i
s
a
a
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
of
o
f
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
is
i
s
considered
c
o
n
s
i
d
e
r
e
d
a
a
finished
f
i
n
i
s
h
e
d
devicewithin
d
e
v
i
c
e
w
i
t
h
i
n
the
t
h
e
meaning
m
e
a
n
i
n
g
of
o
f
the
t
h
e
QS
Q
S
regulation.
r
e
g
u
l
a
t
i
o
n
.
178
1
7
8
Drug
D
r
u
g
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
set
s
e
t
forth
f
o
r
t
h
in
i
n
§
§
3.2(g)
3
.
2
(
g
)
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
A
A
drug
d
r
u
g
that
t
h
a
t
is
i
s
a
a
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
of
o
f
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
is
i
s
considered
c
o
n
s
i
d
e
r
e
d
a
a
drug
d
r
u
g
product
p
r
o
d
u
c
t
within
w
i
t
h
i
n
the
t
h
e
meaning
m
e
a
n
i
n
g
of
o
f
the
t
h
e
drug
d
r
u
g
CGMPs.
C
G
M
P
s
.
Drug
D
r
u
g
CGMPs
C
G
M
P
s
refers
r
e
f
e
r
s
to
t
o
the
t
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
regula-
r
e
g
u
l
a
-
tions
t
i
o
n
s
set
s
e
t
forth
f
o
r
t
h
in
i
n
parts
p
a
r
t
s
210
2
1
0
and
a
n
d
211
2
1
1
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
HCT/Ps
H
C
T
/
P
s
refers
r
e
f
e
r
s
to
t
o
human
h
u
m
a
n
cell,
c
e
l
l
,
tissue,
t
i
s
s
u
e
,
and
a
n
d
cellular
c
e
l
l
u
l
a
r
and
a
n
d
tissue-based
t
i
s
s
u
e
-
b
a
s
e
d
products,
p
r
o
d
u
c
t
s
,
as
a
s
defined
d
e
f
i
n
e
d
in
i
n
§
§
1271.3(d)
1
2
7
1
.
3
(
d
)
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
An
A
n
HCT/P
H
C
T
/
P
that
t
h
a
t
is
i
s
not
n
o
t
solely
s
o
l
e
l
y
regulated
r
e
g
u
l
a
t
e
d
under
u
n
d
e
r
section
s
e
c
t
i
o
n
361
3
6
1
of
o
f
the
t
h
e
Public
P
u
b
l
i
c
Health
H
e
a
l
t
h
Service
S
e
r
v
i
c
e
Act
A
c
t
may
m
a
y
be
b
e
a
a
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
of
o
f
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product.
p
r
o
d
u
c
t
.
Such
S
u
c
h
an
a
n
HCT/P
H
C
T
/
P
is
i
s
subject
s
u
b
j
e
c
t
to
t
o
part
p
a
r
t
1271
1
2
7
1
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
and
a
n
d
is
i
s
also
a
l
s
o
regulated
r
e
g
u
l
a
t
e
d
as
a
s
a
a
drug,
d
r
u
g
,
device,
d
e
v
i
c
e
,
and/or
a
n
d
/
o
r
biological
b
i
o
l
o
g
i
c
a
l
product.
p
r
o
d
u
c
t
.
Manufacture
M
a
n
u
f
a
c
t
u
r
e
includes,
i
n
c
l
u
d
e
s
,
but
b
u
t
is
i
s
not
n
o
t
lim-
l
i
m
-
ited
i
t
e
d
to,
t
o
,
designing,
d
e
s
i
g
n
i
n
g
,
fabricating,
f
a
b
r
i
c
a
t
i
n
g
,
assem-
a
s
s
e
m
-
bling,
b
l
i
n
g
,
filling,
f
i
l
l
i
n
g
,
processing,
p
r
o
c
e
s
s
i
n
g
,
testing,
t
e
s
t
i
n
g
,
label-
l
a
b
e
l
-
ing,
i
n
g
,
packaging,
p
a
c
k
a
g
i
n
g
,
repackaging,
r
e
p
a
c
k
a
g
i
n
g
,
holding,
h
o
l
d
i
n
g
,
and
a
n
d
storage.
s
t
o
r
a
g
e
.
QS
Q
S
regulation
r
e
g
u
l
a
t
i
o
n
refers
r
e
f
e
r
s
to
t
o
the
t
h
e
qualitysystem
q
u
a
l
i
t
y
s
y
s
t
e
m
regulation
r
e
g
u
l
a
t
i
o
n
in
i
n
part
p
a
r
t
820
8
2
0
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Single-entity
S
i
n
g
l
e
-
e
n
t
i
t
y
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
set
s
e
t
forth
f
o
r
t
h
in
i
n
§
§
3.2(e)(1)
3
.
2
(
e
)
(
1
)
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Type
T
y
p
e
of
o
f
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
refers
r
e
f
e
r
s
to
t
o
the
t
h
e
category
c
a
t
e
g
o
r
y
of
o
f
the
t
h
e
constituent
c
o
n
s
t
i
t
u
e
n
t
part,
p
a
r
t
,
which
w
h
i
c
h
can
c
a
n
be
b
e
either
e
i
t
h
e
r
a
a
biological
b
i
o
l
o
g
i
c
a
l
product,
p
r
o
d
u
c
t
,
a
a
de-
d
e
-
vice,
v
i
c
e
,
or
o
r
a
a
drug,
d
r
u
g
,
as
a
s
these
t
h
e
s
e
terms
t
e
r
m
s
are
a
r
e
de-
d
e
-
fined
f
i
n
e
d
under
u
n
d
e
r
this
t
h
i
s
section.
s
e
c
t
i
o
n
.
[78
[
7
8
FR
F
R
4321,
4
3
2
1
,
Jan.
J
a
n
.
22,
2
2
,
2013]
2
0
1
3
]
EFFECTIVE
E
F
F
E
C
T
I
V
E
DATE
D
A
T
E
NOTE:
N
O
T
E
:
At
A
t
89
8
9
FR
F
R
7522,
7
5
2
2
,
Feb.
F
e
b
.
2,
2
,
2024,
2
0
2
4
,
§
§
4.2
4
.
2
was
w
a
s
amended,
a
m
e
n
d
e
d
,
effective
e
f
f
e
c
t
i
v
e
Feb.
F
e
b
.
2,
2
,
2026.
2
0
2
6
.
§
§
4.3
4
.
3
What
W
h
a
t
current
c
u
r
r
e
n
t
good
g
o
o
d
manufac-
m
a
n
u
f
a
c
-
turing
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
apply
a
p
p
l
y
to
t
o
my
m
y
combination
c
o
m
b
i
n
a
t
i
o
n
product?
p
r
o
d
u
c
t
?
If
I
f
you
y
o
u
manufacture
m
a
n
u
f
a
c
t
u
r
e
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product,
p
r
o
d
u
c
t
,
the
t
h
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
listed
l
i
s
t
e
d
in
i
n
this
t
h
i
s
section
s
e
c
t
i
o
n
apply
a
p
p
l
y
as
a
s
follows:
f
o
l
l
o
w
s
:
(a)
(
a
)
The
T
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
in
i
n
parts
p
a
r
t
s
210
2
1
0
and
a
n
d
211
2
1
1
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
apply
a
p
p
l
y
to
t
o
a
a
combina-
c
o
m
b
i
n
a
-
tion
t
i
o
n
product
p
r
o
d
u
c
t
that
t
h
a
t
includes
i
n
c
l
u
d
e
s
a
a
drug
d
r
u
g
con-
c
o
n
-
stituent
s
t
i
t
u
e
n
t
part;
p
a
r
t
;
(b)
(
b
)
The
T
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
in
i
n
part
p
a
r
t
820
8
2
0
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
apply
a
p
p
l
y
to
t
o
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
that
t
h
a
t
includes
i
n
c
l
u
d
e
s
a
a
device
d
e
v
i
c
e
con-
c
o
n
-
stituent
s
t
i
t
u
e
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t
part;
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Food
F
o
o
d
and
a
n
d
Drug
D
r
u
g
Administration,
A
d
m
i
n
i
s
t
r
a
t
i
o
n
,
HHS
H
H
S
§
§
4.4
4
.
4
jspears
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s
p
e
a
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s
on
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DSK121TN23PROD
D
S
K
1
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N
2
3
P
R
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with
w
i
t
h
CFR
C
F
R
(c)
(
c
)
The
T
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
among
a
m
o
n
g
the
t
h
e
re-
r
e
-
quirements
q
u
i
r
e
m
e
n
t
s
(including
(
i
n
c
l
u
d
i
n
g
standards)
s
t
a
n
d
a
r
d
s
)
for
f
o
r
biological
b
i
o
l
o
g
i
c
a
l
products
p
r
o
d
u
c
t
s
in
i
n
parts
p
a
r
t
s
600
6
0
0
through
t
h
r
o
u
g
h
680
6
8
0
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
apply
a
p
p
l
y
to
t
o
a
a
combina-
c
o
m
b
i
n
a
-
tion
t
i
o
n
product
p
r
o
d
u
c
t
that
t
h
a
t
includes
i
n
c
l
u
d
e
s
a
a
biological
b
i
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
to
t
o
which
w
h
i
c
h
those
t
h
o
s
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
would
w
o
u
l
d
apply
a
p
p
l
y
if
i
f
that
t
h
a
t
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
were
w
e
r
e
not
n
o
t
part
p
a
r
t
of
o
f
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product;
p
r
o
d
u
c
t
;
and
a
n
d
(d)
(
d
)
The
T
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
tissue
t
i
s
s
u
e
practice
p
r
a
c
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
including
i
n
c
l
u
d
i
n
g
donor
d
o
n
o
r
eligi-
e
l
i
g
i
-
bility
b
i
l
i
t
y
requirements
r
e
q
u
i
r
e
m
e
n
t
s
for
f
o
r
HCT/Ps
H
C
T
/
P
s
in
i
n
part
p
a
r
t
1271
1
2
7
1
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
apply
a
p
p
l
y
to
t
o
a
a
combina-
c
o
m
b
i
n
a
-
tion
t
i
o
n
product
p
r
o
d
u
c
t
that
t
h
a
t
includes
i
n
c
l
u
d
e
s
an
a
n
HCT/P.
H
C
T
/
P
.
EFFECTIVE
E
F
F
E
C
T
I
V
E
DATE
D
A
T
E
NOTE:
N
O
T
E
:
Amendments
A
m
e
n
d
m
e
n
t
s
to
t
o
§
§
4.3
4
.
3
were
w
e
r
e
published
p
u
b
l
i
s
h
e
d
at
a
t
89
8
9
FR
F
R
51765,
5
1
7
6
5
,
June
J
u
n
e
18,
1
8
,
2024,
2
0
2
4
,
effective
e
f
f
e
c
t
i
v
e
Feb.
F
e
b
.
2,
2
,
2026.
2
0
2
6
.
§
§
4.4
4
.
4
How
H
o
w
can
c
a
n
I
I
comply
c
o
m
p
l
y
with
w
i
t
h
these
t
h
e
s
e
cur-
c
u
r
-
rent
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
for
f
o
r
a
a
co-packaged
c
o
-
p
a
c
k
a
g
e
d
or
o
r
single-entity
s
i
n
g
l
e
-
e
n
t
i
t
y
combination
c
o
m
b
i
n
a
t
i
o
n
product?
p
r
o
d
u
c
t
?
(a)
(
a
)
Under
U
n
d
e
r
this
t
h
i
s
subpart,
s
u
b
p
a
r
t
,
for
f
o
r
single
s
i
n
g
l
e
en-
e
n
-
tity
t
i
t
y
or
o
r
co-packaged
c
o
-
p
a
c
k
a
g
e
d
combination
c
o
m
b
i
n
a
t
i
o
n
prod-
p
r
o
d
-
ucts,
u
c
t
s
,
compliance
c
o
m
p
l
i
a
n
c
e
with
w
i
t
h
all
a
l
l
applicable
a
p
p
l
i
c
a
b
l
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
for
f
o
r
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
prod-
p
r
o
d
-
uct
u
c
t
shall
s
h
a
l
l
be
b
e
achieved
a
c
h
i
e
v
e
d
through
t
h
r
o
u
g
h
the
t
h
e
de-
d
e
-
sign
s
i
g
n
and
a
n
d
implementation
i
m
p
l
e
m
e
n
t
a
t
i
o
n
of
o
f
a
a
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
that
t
h
a
t
is
i
s
demonstrated
d
e
m
o
n
s
t
r
a
t
e
d
to
t
o
comply
c
o
m
p
l
y
with:
w
i
t
h
:
-
The
T
h
e
specifics
s
p
e
c
i
f
i
c
s
of
o
f
each
e
a
c
h
set
s
e
t
of
o
f
cur-
c
u
r
-
rent
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
regu-
r
e
g
u
-
lations
l
a
t
i
o
n
s
listed
l
i
s
t
e
d
under
u
n
d
e
r
§
§
4.3
4
.
3
as
a
s
they
t
h
e
y
apply
a
p
p
l
y
to
t
o
each
e
a
c
h
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
included
i
n
c
l
u
d
e
d
in
i
n
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product;
p
r
o
d
u
c
t
;
or
o
r
-
Paragraph
P
a
r
a
g
r
a
p
h
(b)
(
b
)
of
o
f
this
t
h
i
s
section.
s
e
c
t
i
o
n
.
(b)
(
b
)
If
I
f
you
y
o
u
elect
e
l
e
c
t
to
t
o
establish
e
s
t
a
b
l
i
s
h
a
a
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
in
i
n
accordance
a
c
c
o
r
d
a
n
c
e
with
w
i
t
h
paragraph
p
a
r
a
g
r
a
p
h
(b)
(
b
)
of
o
f
this
t
h
i
s
section,
s
e
c
t
i
o
n
,
the
t
h
e
following
f
o
l
l
o
w
i
n
g
re-
r
e
-
quirements
q
u
i
r
e
m
e
n
t
s
apply:
a
p
p
l
y
:
-
If
I
f
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
in-
i
n
-
cludes
c
l
u
d
e
s
a
a
device
d
e
v
i
c
e
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
and
a
n
d
a
a
drug
d
r
u
g
constituent
c
o
n
s
t
i
t
u
e
n
t
part,
p
a
r
t
,
and
a
n
d
the
t
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
has
h
a
s
been
b
e
e
n
shown
s
h
o
w
n
to
t
o
comply
c
o
m
p
l
y
with
w
i
t
h
the
t
h
e
drug
d
r
u
g
CGMPs,
C
G
M
P
s
,
the
t
h
e
following
f
o
l
l
o
w
i
n
g
provi-
p
r
o
v
i
-
sions
s
i
o
n
s
of
o
f
the
t
h
e
QS
Q
S
regulation
r
e
g
u
l
a
t
i
o
n
must
m
u
s
t
also
a
l
s
o
be
b
e
shown
s
h
o
w
n
to
t
o
have
h
a
v
e
been
b
e
e
n
satisfied;
s
a
t
i
s
f
i
e
d
;
upon
u
p
o
n
demonstration
d
e
m
o
n
s
t
r
a
t
i
o
n
that
t
h
a
t
these
t
h
e
s
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
have
h
a
v
e
been
b
e
e
n
satisfied,
s
a
t
i
s
f
i
e
d
,
no
n
o
additional
a
d
d
i
t
i
o
n
a
l
showing
s
h
o
w
i
n
g
of
o
f
compliance
c
o
m
p
l
i
a
n
c
e
with
w
i
t
h
respect
r
e
s
p
e
c
t
to
t
o
the
t
h
e
QS
Q
S
regulation
r
e
g
u
l
a
t
i
o
n
need
n
e
e
d
be
b
e
made:
m
a
d
e
:
(i)
(
i
)
Section
S
e
c
t
i
o
n
820.20
8
2
0
.
2
0
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Management
M
a
n
a
g
e
m
e
n
t
responsibility.
r
e
s
p
o
n
s
i
b
i
l
i
t
y
.
179
1
7
9
(ii)
(
i
i
)
Section
S
e
c
t
i
o
n
820.30
8
2
0
.
3
0
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
De-
D
e
-
sign
s
i
g
n
controls.
c
o
n
t
r
o
l
s
.
(iii)
(
i
i
i
)
Section
S
e
c
t
i
o
n
820.50
8
2
0
.
5
0
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Purchasing
P
u
r
c
h
a
s
i
n
g
controls.
c
o
n
t
r
o
l
s
.
(iv)
(
i
v
)
Section
S
e
c
t
i
o
n
820.100
8
2
0
.
1
0
0
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Corrective
C
o
r
r
e
c
t
i
v
e
and
a
n
d
preventive
p
r
e
v
e
n
t
i
v
e
action.
a
c
t
i
o
n
.
(v)
(
v
)
Section
S
e
c
t
i
o
n
820.170
8
2
0
.
1
7
0
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
In-
I
n
-
stallation.
s
t
a
l
l
a
t
i
o
n
.
(vi)
(
v
i
)
Section
S
e
c
t
i
o
n
820.200
8
2
0
.
2
0
0
of
o
f
this
t
h
i
s
chap-
c
h
a
p
-
ter.Servicing.
t
e
r
.
S
e
r
v
i
c
i
n
g
.
-
If
I
f
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
in-
i
n
-
cludes
c
l
u
d
e
s
a
a
device
d
e
v
i
c
e
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
and
a
n
d
a
a
drug
d
r
u
g
constituent
c
o
n
s
t
i
t
u
e
n
t
part,
p
a
r
t
,
and
a
n
d
the
t
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
has
h
a
s
been
b
e
e
n
shown
s
h
o
w
n
to
t
o
comply
c
o
m
p
l
y
with
w
i
t
h
the
t
h
e
QS
Q
S
regulation,
r
e
g
u
l
a
t
i
o
n
,
the
t
h
e
following
f
o
l
l
o
w
i
n
g
provi-
p
r
o
v
i
-
sions
s
i
o
n
s
of
o
f
the
t
h
e
drug
d
r
u
g
CGMPs
C
G
M
P
s
must
m
u
s
t
also
a
l
s
o
be
b
e
shown
s
h
o
w
n
to
t
o
have
h
a
v
e
been
b
e
e
n
satisfied;
s
a
t
i
s
f
i
e
d
;
upon
u
p
o
n
demonstration
d
e
m
o
n
s
t
r
a
t
i
o
n
that
t
h
a
t
these
t
h
e
s
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
have
h
a
v
e
been
b
e
e
n
satisfied,
s
a
t
i
s
f
i
e
d
,
no
n
o
additional
a
d
d
i
t
i
o
n
a
l
showing
s
h
o
w
i
n
g
of
o
f
compliance
c
o
m
p
l
i
a
n
c
e
with
w
i
t
h
respect
r
e
s
p
e
c
t
to
t
o
the
t
h
e
drug
d
r
u
g
CGMPs
C
G
M
P
s
need
n
e
e
d
be
b
e
made:
m
a
d
e
:
(i)
(
i
)
Section
S
e
c
t
i
o
n
211.84
2
1
1
.
8
4
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Testing
T
e
s
t
i
n
g
and
a
n
d
approval
a
p
p
r
o
v
a
l
or
o
r
rejection
r
e
j
e
c
t
i
o
n
of
o
f
components,
c
o
m
p
o
n
e
n
t
s
,
drug
d
r
u
g
product
p
r
o
d
u
c
t
containers,
c
o
n
t
a
i
n
e
r
s
,
and
a
n
d
closures.
c
l
o
s
u
r
e
s
.
(ii)
(
i
i
)
Section
S
e
c
t
i
o
n
211.103
2
1
1
.
1
0
3
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Calculation
C
a
l
c
u
l
a
t
i
o
n
of
o
f
yield.
y
i
e
l
d
.
(iii)
(
i
i
i
)
Section
S
e
c
t
i
o
n
211.132
2
1
1
.
1
3
2
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Tamper-evident
T
a
m
p
e
r
-
e
v
i
d
e
n
t
packaging
p
a
c
k
a
g
i
n
g
require-
r
e
q
u
i
r
e
-
ments
m
e
n
t
s
for
f
o
r
over-the-counter
o
v
e
r
-
t
h
e
-
c
o
u
n
t
e
r
(OTC)
(
O
T
C
)
human
h
u
m
a
n
drug
d
r
u
g
products.
p
r
o
d
u
c
t
s
.
(iv)
(
i
v
)
Section
S
e
c
t
i
o
n
211.137
2
1
1
.
1
3
7
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Expiration
E
x
p
i
r
a
t
i
o
n
dating.
d
a
t
i
n
g
.
(v)
(
v
)
Section
S
e
c
t
i
o
n
211.165
2
1
1
.
1
6
5
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Testing
T
e
s
t
i
n
g
and
a
n
d
release
r
e
l
e
a
s
e
for
f
o
r
distribution.
d
i
s
t
r
i
b
u
t
i
o
n
.
(vi)
(
v
i
)
Section
S
e
c
t
i
o
n
211.166
2
1
1
.
1
6
6
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Stability
S
t
a
b
i
l
i
t
y
testing.
t
e
s
t
i
n
g
.
(vii)
(
v
i
i
)
Section
S
e
c
t
i
o
n
211.167
2
1
1
.
1
6
7
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Special
S
p
e
c
i
a
l
testing
t
e
s
t
i
n
g
requirements.
r
e
q
u
i
r
e
m
e
n
t
s
.
(viii)
(
v
i
i
i
)
Section
S
e
c
t
i
o
n
211.170
2
1
1
.
1
7
0
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Reserve
R
e
s
e
r
v
e
samples.
s
a
m
p
l
e
s
.
-
In
I
n
addition
a
d
d
i
t
i
o
n
to
t
o
being
b
e
i
n
g
shown
s
h
o
w
n
to
t
o
comply
c
o
m
p
l
y
with
w
i
t
h
the
t
h
e
other
o
t
h
e
r
applicable
a
p
p
l
i
c
a
b
l
e
man-
m
a
n
-
ufacturing
u
f
a
c
t
u
r
i
n
g
requirements
r
e
q
u
i
r
e
m
e
n
t
s
listed
l
i
s
t
e
d
under
u
n
d
e
r
§
§
4.3,
4
.
3
,
if
i
f
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
in-
i
n
-
cludes
c
l
u
d
e
s
a
a
biological
b
i
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
constituent
c
o
n
s
t
i
t
u
e
n
t
part,
p
a
r
t
,
the
t
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
must
m
u
s
t
also
a
l
s
o
be
b
e
shown
s
h
o
w
n
to
t
o
implement
i
m
p
l
e
m
e
n
t
and
a
n
d
comply
c
o
m
p
l
y
with
w
i
t
h
all
a
l
l
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
requirements
r
e
q
u
i
r
e
m
e
n
t
s
identi-
i
d
e
n
t
i
-
fied
f
i
e
d
under
u
n
d
e
r
§
§
4.3(c)
4
.
3
(
c
)
that
t
h
a
t
would
w
o
u
l
d
apply
a
p
p
l
y
to
t
o
that
t
h
a
t
biological
b
i
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
if
i
f
that
t
h
a
t
con-
c
o
n
-
stituent
s
t
i
t
u
e
n
t
part
p
a
r
t
were
w
e
r
e
not
n
o
t
part
p
a
r
t
of
o
f
a
a
com-
c
o
m
-
bination
b
i
n
a
t
i
o
n
product.
p
r
o
d
u
c
t
.
-
In
I
n
addition
a
d
d
i
t
i
o
n
to
t
o
being
b
e
i
n
g
shown
s
h
o
w
n
to
t
o
comply
c
o
m
p
l
y
with
w
i
t
h
the
t
h
e
other
o
t
h
e
r
applicable
a
p
p
l
i
c
a
b
l
e
cur-
c
u
r
-
rent
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
re-
r
e
-
quirements
q
u
i
r
e
m
e
n
t
s
listed
l
i
s
t
e
d
under
u
n
d
e
r
§
§
4.3,
4
.
3
,
if
i
f
the
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§
§
4.100
4
.
1
0
0
21
2
1
CFR
C
F
R
Ch.
C
h
.
I
I
(4–1–25
(
4
–
1
–
2
5
Edition)
E
d
i
t
i
o
n
)
jspears
j
s
p
e
a
r
s
on
o
n
DSK121TN23PROD
D
S
K
1
2
1
T
N
2
3
P
R
O
D
with
w
i
t
h
CFR
C
F
R
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
includes
i
n
c
l
u
d
e
s
an
a
n
HCT/
H
C
T
/
P,
P
,
the
t
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
must
m
u
s
t
also
a
l
s
o
be
b
e
shown
s
h
o
w
n
to
t
o
implement
i
m
p
l
e
m
e
n
t
and
a
n
d
comply
c
o
m
p
l
y
with
w
i
t
h
all
a
l
l
current
c
u
r
r
e
n
t
good
g
o
o
d
tissue
t
i
s
s
u
e
practice
p
r
a
c
t
i
c
e
re-
r
e
-
quirements
q
u
i
r
e
m
e
n
t
s
identified
i
d
e
n
t
i
f
i
e
d
under
u
n
d
e
r
§
§
4.3(d)
4
.
3
(
d
)
that
t
h
a
t
would
w
o
u
l
d
apply
a
p
p
l
y
to
t
o
that
t
h
a
t
HCT/P
H
C
T
/
P
if
i
f
it
i
t
were
w
e
r
e
not
n
o
t
part
p
a
r
t
of
o
f
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
prod-
p
r
o
d
-
uct.
u
c
t
.
(c)
(
c
)
During
D
u
r
i
n
g
any
a
n
y
period
p
e
r
i
o
d
in
i
n
which
w
h
i
c
h
the
t
h
e
manufacture
m
a
n
u
f
a
c
t
u
r
e
of
o
f
a
a
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
to
t
o
be
b
e
included
i
n
c
l
u
d
e
d
in
i
n
a
a
co-packaged
c
o
-
p
a
c
k
a
g
e
d
or
o
r
single
s
i
n
g
l
e
entity
e
n
t
i
t
y
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
occurs
o
c
c
u
r
s
at
a
t
a
a
separate
s
e
p
a
r
a
t
e
facility
f
a
c
i
l
i
t
y
from
f
r
o
m
the
t
h
e
other
o
t
h
e
r
con-
c
o
n
-
stituent
s
t
i
t
u
e
n
t
part(s)
p
a
r
t
(
s
)
to
t
o
be
b
e
included
i
n
c
l
u
d
e
d
in
i
n
that
t
h
a
t
single-entity
s
i
n
g
l
e
-
e
n
t
i
t
y
or
o
r
co-packaged
c
o
-
p
a
c
k
a
g
e
d
combina-
c
o
m
b
i
n
a
-
tion
t
i
o
n
product,
p
r
o
d
u
c
t
,
the
t
h
e
current
c
u
r
r
e
n
t
good
g
o
o
d
manu-
m
a
n
u
-
facturing
f
a
c
t
u
r
i
n
g
practice
p
r
a
c
t
i
c
e
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
for
f
o
r
that
t
h
a
t
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
at
a
t
that
t
h
a
t
facility
f
a
c
i
l
i
t
y
must
m
u
s
t
be
b
e
demonstrated
d
e
m
o
n
s
t
r
a
t
e
d
to
t
o
comply
c
o
m
p
l
y
with
w
i
t
h
all
a
l
l
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
prac-
p
r
a
c
-
tice
t
i
c
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
that
t
h
a
t
type
t
y
p
e
of
o
f
constituent
c
o
n
s
t
i
t
u
e
n
t
part.
p
a
r
t
.
(d)
(
d
)
When
W
h
e
n
two
t
w
o
or
o
r
more
m
o
r
e
types
t
y
p
e
s
of
o
f
con-
c
o
n
-
stituent
s
t
i
t
u
e
n
t
parts
p
a
r
t
s
to
t
o
be
b
e
included
i
n
c
l
u
d
e
d
in
i
n
a
a
sin-
s
i
n
-
gle-entity
g
l
e
-
e
n
t
i
t
y
or
o
r
co-packaged
c
o
-
p
a
c
k
a
g
e
d
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
have
h
a
v
e
arrived
a
r
r
i
v
e
d
at
a
t
the
t
h
e
same
s
a
m
e
facil-
f
a
c
i
l
-
ity,
i
t
y
,
or
o
r
the
t
h
e
manufacture
m
a
n
u
f
a
c
t
u
r
e
of
o
f
these
t
h
e
s
e
con-
c
o
n
-
stituent
s
t
i
t
u
e
n
t
parts
p
a
r
t
s
is
i
s
proceeding
p
r
o
c
e
e
d
i
n
g
at
a
t
the
t
h
e
same
s
a
m
e
facility,
f
a
c
i
l
i
t
y
,
application
a
p
p
l
i
c
a
t
i
o
n
of
o
f
a
a
current
c
u
r
r
e
n
t
good
g
o
o
d
manufacturing
m
a
n
u
f
a
c
t
u
r
i
n
g
process
p
r
o
c
e
s
s
operating
o
p
e
r
a
t
i
n
g
system
s
y
s
t
e
m
that
t
h
a
t
complies
c
o
m
p
l
i
e
s
with
w
i
t
h
paragraph
p
a
r
a
g
r
a
p
h
(b)
(
b
)
of
o
f
this
t
h
i
s
section
s
e
c
t
i
o
n
may
m
a
y
begin.
b
e
g
i
n
.
(e)
(
e
)
The
T
h
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
set
s
e
t
forth
f
o
r
t
h
in
i
n
this
t
h
i
s
subpart
s
u
b
p
a
r
t
and
a
n
d
in
i
n
parts
p
a
r
t
s
210,
2
1
0
,
211,
2
1
1
,
820,
8
2
0
,
600
6
0
0
through
t
h
r
o
u
g
h
680,
6
8
0
,
and
a
n
d
1271
1
2
7
1
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
listed
l
i
s
t
e
d
in
i
n
§
§
4.3,
4
.
3
,
supplement,
s
u
p
p
l
e
m
e
n
t
,
and
a
n
d
do
d
o
not
n
o
t
supersede,
s
u
p
e
r
s
e
d
e
,
each
e
a
c
h
other
o
t
h
e
r
unless
u
n
l
e
s
s
the
t
h
e
regu-
r
e
g
u
-
lations
l
a
t
i
o
n
s
explicitly
e
x
p
l
i
c
i
t
l
y
provide
p
r
o
v
i
d
e
otherwise.
o
t
h
e
r
w
i
s
e
.
In
I
n
the
t
h
e
event
e
v
e
n
t
of
o
f
a
a
conflict
c
o
n
f
l
i
c
t
between
b
e
t
w
e
e
n
regula-
r
e
g
u
l
a
-
tions
t
i
o
n
s
applicable
a
p
p
l
i
c
a
b
l
e
under
u
n
d
e
r
this
t
h
i
s
subpart
s
u
b
p
a
r
t
to
t
o
combination
c
o
m
b
i
n
a
t
i
o
n
products,
p
r
o
d
u
c
t
s
,
including
i
n
c
l
u
d
i
n
g
their
t
h
e
i
r
constituent
c
o
n
s
t
i
t
u
e
n
t
parts,
p
a
r
t
s
,
the
t
h
e
regulations
r
e
g
u
l
a
t
i
o
n
s
most
m
o
s
t
specifically
s
p
e
c
i
f
i
c
a
l
l
y
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
the
t
h
e
con-
c
o
n
-
stituent
s
t
i
t
u
e
n
t
part
p
a
r
t
in
i
n
question
q
u
e
s
t
i
o
n
shall
s
h
a
l
l
super-
s
u
p
e
r
-
sede
s
e
d
e
the
t
h
e
more
m
o
r
e
general.
g
e
n
e
r
a
l
.
[78
[
7
8
FR
F
R
4321,
4
3
2
1
,
Jan.
J
a
n
.
22,
2
2
,
2013]
2
0
1
3
]
EFFECTIVE
E
F
F
E
C
T
I
V
E
DATE
D
A
T
E
NOTE:
N
O
T
E
:
Amendments
A
m
e
n
d
m
e
n
t
s
to
t
o
§
§
4.4
4
.
4
were
w
e
r
e
published
p
u
b
l
i
s
h
e
d
at
a
t
89
8
9
FR
F
R
7522,
7
5
2
2
,
Feb.
F
e
b
.
2,
2
,
2024,
2
0
2
4
,
and
a
n
d
at
a
t
89
8
9
FR
F
R
51766,
5
1
7
6
6
,
June.
J
u
n
e
.
18,
1
8
,
2024,
2
0
2
4
,
effective
e
f
f
e
c
t
i
v
e
Feb.
F
e
b
.
2,
2
,
2026.
2
0
2
6
.
Subpart
S
u
b
p
a
r
t
B—Postmarketing
B
—
P
o
s
t
m
a
r
k
e
t
i
n
g
Safety
S
a
f
e
t
y
Reporting
R
e
p
o
r
t
i
n
g
for
f
o
r
Combination
C
o
m
b
i
n
a
t
i
o
n
Products
P
r
o
d
u
c
t
s
SOURCE:
S
O
U
R
C
E
:
81
8
1
FR
F
R
92624,
9
2
6
2
4
,
Dec.
D
e
c
.
20,
2
0
,
2016,
2
0
1
6
,
unless
u
n
l
e
s
s
otherwise
o
t
h
e
r
w
i
s
e
noted.
n
o
t
e
d
.
180
1
8
0
§
§
4.100
4
.
1
0
0
What
W
h
a
t
is
i
s
the
t
h
e
scope
s
c
o
p
e
of
o
f
this
t
h
i
s
sub-
s
u
b
-
part?
p
a
r
t
?
(a)
(
a
)
This
T
h
i
s
subpart
s
u
b
p
a
r
t
identifies
i
d
e
n
t
i
f
i
e
s
post-
p
o
s
t
-
marketing
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reporting
r
e
p
o
r
t
i
n
g
require-
r
e
q
u
i
r
e
-
ments
m
e
n
t
s
for
f
o
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
appli-
a
p
p
l
i
-
cants
c
a
n
t
s
and
a
n
d
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
applicants.
a
p
p
l
i
c
a
n
t
s
.
(b)
(
b
)
This
T
h
i
s
subpart
s
u
b
p
a
r
t
does
d
o
e
s
not
n
o
t
apply
a
p
p
l
y
to
t
o
in-
i
n
-
vestigational
v
e
s
t
i
g
a
t
i
o
n
a
l
combination
c
o
m
b
i
n
a
t
i
o
n
products,
p
r
o
d
u
c
t
s
,
combination
c
o
m
b
i
n
a
t
i
o
n
products
p
r
o
d
u
c
t
s
that
t
h
a
t
have
h
a
v
e
not
n
o
t
re-
r
e
-
ceived
c
e
i
v
e
d
marketing
m
a
r
k
e
t
i
n
g
authorization,
a
u
t
h
o
r
i
z
a
t
i
o
n
,
or
o
r
to
t
o
persons
p
e
r
s
o
n
s
other
o
t
h
e
r
than
t
h
a
n
combination
c
o
m
b
i
n
a
t
i
o
n
prod-
p
r
o
d
-
uct
u
c
t
applicants
a
p
p
l
i
c
a
n
t
s
and
a
n
d
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
ap-
a
p
-
plicants.
p
l
i
c
a
n
t
s
.
(c)
(
c
)
This
T
h
i
s
subpart
s
u
b
p
a
r
t
supplements
s
u
p
p
l
e
m
e
n
t
s
and
a
n
d
does
d
o
e
s
not
n
o
t
supersede
s
u
p
e
r
s
e
d
e
other
o
t
h
e
r
provisions
p
r
o
v
i
s
i
o
n
s
of
o
f
this
t
h
i
s
chapter,
c
h
a
p
t
e
r
,
including
i
n
c
l
u
d
i
n
g
the
t
h
e
provisions
p
r
o
v
i
s
i
o
n
s
in
i
n
parts
p
a
r
t
s
314,
3
1
4
,
600,
6
0
0
,
606,
6
0
6
,
803,
8
0
3
,
and
a
n
d
806
8
0
6
of
o
f
this
t
h
i
s
chapter,
c
h
a
p
t
e
r
,
unless
u
n
l
e
s
s
a
a
regulation
r
e
g
u
l
a
t
i
o
n
explicitly
e
x
p
l
i
c
i
t
l
y
provides
p
r
o
v
i
d
e
s
otherwise.
o
t
h
e
r
w
i
s
e
.
§
§
4.101
4
.
1
0
1
How
H
o
w
does
d
o
e
s
the
t
h
e
FDA
F
D
A
define
d
e
f
i
n
e
key
k
e
y
terms
t
e
r
m
s
and
a
n
d
phrases
p
h
r
a
s
e
s
in
i
n
this
t
h
i
s
subpart?
s
u
b
p
a
r
t
?
Abbreviated
A
b
b
r
e
v
i
a
t
e
d
new
n
e
w
drug
d
r
u
g
application
a
p
p
l
i
c
a
t
i
o
n
(ANDA)
(
A
N
D
A
)
has
h
a
s
the
t
h
e
same
s
a
m
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
‘‘abbreviated
‘
‘
a
b
b
r
e
v
i
a
t
e
d
application’’
a
p
p
l
i
c
a
t
i
o
n
’
’
in
i
n
§
§
314.3(b)
3
1
4
.
3
(
b
)
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Agency
A
g
e
n
c
y
or
o
r
we
w
e
means
m
e
a
n
s
Food
F
o
o
d
and
a
n
d
Drug
D
r
u
g
Administration.
A
d
m
i
n
i
s
t
r
a
t
i
o
n
.
Applicant
A
p
p
l
i
c
a
n
t
means,
m
e
a
n
s
,
for
f
o
r
the
t
h
e
purposes
p
u
r
p
o
s
e
s
of
o
f
this
t
h
i
s
subpart,
s
u
b
p
a
r
t
,
a
a
person
p
e
r
s
o
n
holding
h
o
l
d
i
n
g
an
a
n
appli-
a
p
p
l
i
-
cation
c
a
t
i
o
n
under
u
n
d
e
r
which
w
h
i
c
h
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
or
o
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
of
o
f
a
a
com-
c
o
m
-
bination
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
has
h
a
s
received
r
e
c
e
i
v
e
d
mar-
m
a
r
-
keting
k
e
t
i
n
g
authorization
a
u
t
h
o
r
i
z
a
t
i
o
n
(such
(
s
u
c
h
as
a
s
approval,
a
p
p
r
o
v
a
l
,
licensure,
l
i
c
e
n
s
u
r
e
,
or
o
r
clearance).
c
l
e
a
r
a
n
c
e
)
.
For
F
o
r
the
t
h
e
pur-
p
u
r
-
poses
p
o
s
e
s
of
o
f
this
t
h
i
s
subpart,
s
u
b
p
a
r
t
,
applicant
a
p
p
l
i
c
a
n
t
is
i
s
used
u
s
e
d
interchangeably
i
n
t
e
r
c
h
a
n
g
e
a
b
l
y
with
w
i
t
h
the
t
h
e
term
t
e
r
m
‘‘you.’’
‘
‘
y
o
u
.
’
’
Application
A
p
p
l
i
c
a
t
i
o
n
means,
m
e
a
n
s
,
for
f
o
r
purposes
p
u
r
p
o
s
e
s
of
o
f
this
t
h
i
s
subpart,
s
u
b
p
a
r
t
,
a
a
BLA,
B
L
A
,
an
a
n
NDA,
N
D
A
,
an
a
n
ANDA,
A
N
D
A
,
or
o
r
a
a
device
d
e
v
i
c
e
application,
a
p
p
l
i
c
a
t
i
o
n
,
includ-
i
n
c
l
u
d
-
ing
i
n
g
all
a
l
l
amendments
a
m
e
n
d
m
e
n
t
s
and
a
n
d
supplements
s
u
p
p
l
e
m
e
n
t
s
to
t
o
them.
t
h
e
m
.
Biological
B
i
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
in
i
n
section
s
e
c
t
i
o
n
351
3
5
1
of
o
f
the
t
h
e
Public
P
u
b
l
i
c
Health
H
e
a
l
t
h
Service
S
e
r
v
i
c
e
Act
A
c
t
(42
(
4
2
U.S.C.
U
.
S
.
C
.
262).
2
6
2
)
.
Biological
B
i
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
deviation
d
e
v
i
a
t
i
o
n
report
r
e
p
o
r
t
(BPDR)
(
B
P
D
R
)
is
i
s
a
a
report
r
e
p
o
r
t
as
a
s
described
d
e
s
c
r
i
b
e
d
in
i
n
§§
§
§
600.14
6
0
0
.
1
4
and
a
n
d
606.171
6
0
6
.
1
7
1
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Biologics
B
i
o
l
o
g
i
c
s
license
l
i
c
e
n
s
e
application
a
p
p
l
i
c
a
t
i
o
n
(BLA)
(
B
L
A
)
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
in
i
n
section
s
e
c
t
i
o
n
351
3
5
1
of
o
f
the
t
h
e
Public
P
u
b
l
i
c
Health
H
e
a
l
t
h
Service
S
e
r
v
i
c
e
Act
A
c
t
(42
(
4
2
U.S.C.
U
.
S
.
C
.
262)
2
6
2
)
and
a
n
d
§
§
601.2
6
0
1
.
2
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Combination
C
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
in
i
n
§
§
3.2(e)
3
.
2
(
e
)
of
o
f
this
t
h
i
s
chap-
c
h
a
p
-
ter.
t
e
r
.
Combination
C
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicant
a
p
p
l
i
c
a
n
t
means
m
e
a
n
s
an
a
n
applicant
a
p
p
l
i
c
a
n
t
that
t
h
a
t
holds
h
o
l
d
s
the
t
h
e
applica-
a
p
p
l
i
c
a
-
tion(s)
t
i
o
n
(
s
)
for
f
o
r
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product.
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r
o
d
u
c
t
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F
o
o
d
and
a
n
d
Drug
D
r
u
g
Administration,
A
d
m
i
n
i
s
t
r
a
t
i
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n
,
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H
H
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i
t
h
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C
F
R
Constituent
C
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
in
i
n
§
§
4.2.
4
.
2
.
Constituent
C
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
applicant
a
p
p
l
i
c
a
n
t
means
m
e
a
n
s
the
t
h
e
applicant
a
p
p
l
i
c
a
n
t
for
f
o
r
a
a
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
of
o
f
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
the
t
h
e
constituent
c
o
n
s
t
i
t
u
e
n
t
parts
p
a
r
t
s
of
o
f
which
w
h
i
c
h
are
a
r
e
marketed
m
a
r
k
e
t
e
d
under
u
n
d
e
r
ap-
a
p
-
plications
p
l
i
c
a
t
i
o
n
s
held
h
e
l
d
by
b
y
different
d
i
f
f
e
r
e
n
t
applicants.
a
p
p
l
i
c
a
n
t
s
.
Correction
C
o
r
r
e
c
t
i
o
n
or
o
r
removal
r
e
m
o
v
a
l
report
r
e
p
o
r
t
is
i
s
a
a
report
r
e
p
o
r
t
as
a
s
described
d
e
s
c
r
i
b
e
d
in
i
n
§
§
806.10
8
0
6
.
1
0
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
De
D
e
novo
n
o
v
o
classification
c
l
a
s
s
i
f
i
c
a
t
i
o
n
request
r
e
q
u
e
s
t
is
i
s
a
a
sub-
s
u
b
-
mission
m
i
s
s
i
o
n
requesting
r
e
q
u
e
s
t
i
n
g
de
d
e
novo
n
o
v
o
classifica-
c
l
a
s
s
i
f
i
c
a
-
tion
t
i
o
n
under
u
n
d
e
r
section
s
e
c
t
i
o
n
513(f)(2)
5
1
3
(
f
)
(
2
)
of
o
f
the
t
h
e
Fed-
F
e
d
-
eral
e
r
a
l
Food,
F
o
o
d
,
Drug,
D
r
u
g
,
and
a
n
d
Cosmetic
C
o
s
m
e
t
i
c
Act.
A
c
t
.
Device
D
e
v
i
c
e
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
in
i
n
section
s
e
c
t
i
o
n
201(h)
2
0
1
(
h
)
of
o
f
the
t
h
e
Federal
F
e
d
e
r
a
l
Food,
F
o
o
d
,
Drug,
D
r
u
g
,
and
a
n
d
Cosmetic
C
o
s
m
e
t
i
c
Act.
A
c
t
.
Device
D
e
v
i
c
e
application
a
p
p
l
i
c
a
t
i
o
n
means
m
e
a
n
s
a
a
PMA,
P
M
A
,
PDP,
P
D
P
,
premarket
p
r
e
m
a
r
k
e
t
notification
n
o
t
i
f
i
c
a
t
i
o
n
submis-
s
u
b
m
i
s
-
sion,
s
i
o
n
,
de
d
e
novo
n
o
v
o
classification
c
l
a
s
s
i
f
i
c
a
t
i
o
n
request,
r
e
q
u
e
s
t
,
or
o
r
HDE.
H
D
E
.
Drug
D
r
u
g
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
in
i
n
section
s
e
c
t
i
o
n
201(g)(1)
2
0
1
(
g
)
(
1
)
of
o
f
the
t
h
e
Federal
F
e
d
e
r
a
l
Food,
F
o
o
d
,
Drug,
D
r
u
g
,
and
a
n
d
Cosmetic
C
o
s
m
e
t
i
c
Act.
A
c
t
.
Field
F
i
e
l
d
alert
a
l
e
r
t
report
r
e
p
o
r
t
is
i
s
a
a
report
r
e
p
o
r
t
as
a
s
de-
d
e
-
scribed
s
c
r
i
b
e
d
in
i
n
§
§
314.81
3
1
4
.
8
1
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Fifteen-day
F
i
f
t
e
e
n
-
d
a
y
report
r
e
p
o
r
t
is
i
s
a
a
report
r
e
p
o
r
t
required
r
e
q
u
i
r
e
d
to
t
o
be
b
e
submitted
s
u
b
m
i
t
t
e
d
within
w
i
t
h
i
n
15
1
5
days
d
a
y
s
as
a
s
de-
d
e
-
scribed
s
c
r
i
b
e
d
in
i
n
§
§
314.80
3
1
4
.
8
0
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
or
o
r
§
§
600.80
6
0
0
.
8
0
of
o
f
this
t
h
i
s
chapter,
c
h
a
p
t
e
r
,
as
a
s
well
w
e
l
l
as
a
s
fol-
f
o
l
-
lowup
l
o
w
u
p
reports
r
e
p
o
r
t
s
to
t
o
such
s
u
c
h
a
a
report.
r
e
p
o
r
t
.
Five-day
F
i
v
e
-
d
a
y
report
r
e
p
o
r
t
is
i
s
a
a
report
r
e
p
o
r
t
as
a
s
de-
d
e
-
scribed
s
c
r
i
b
e
d
in
i
n
§§
§
§
803.3
8
0
3
.
3
and
a
n
d
803.53
8
0
3
.
5
3
of
o
f
this
t
h
i
s
chapter,
c
h
a
p
t
e
r
,
as
a
s
well
w
e
l
l
as
a
s
supplemental
s
u
p
p
l
e
m
e
n
t
a
l
or
o
r
fol-
f
o
l
-
lowup
l
o
w
u
p
reports
r
e
p
o
r
t
s
to
t
o
such
s
u
c
h
a
a
report
r
e
p
o
r
t
as
a
s
de-
d
e
-
scribed
s
c
r
i
b
e
d
in
i
n
§
§
803.56
8
0
3
.
5
6
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Humanitarian
H
u
m
a
n
i
t
a
r
i
a
n
device
d
e
v
i
c
e
exemption
e
x
e
m
p
t
i
o
n
(HDE)
(
H
D
E
)
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
in
i
n
§
§
814.3
8
1
4
.
3
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Malfunction
M
a
l
f
u
n
c
t
i
o
n
report
r
e
p
o
r
t
is
i
s
a
a
report
r
e
p
o
r
t
as
a
s
de-
d
e
-
scribed
s
c
r
i
b
e
d
in
i
n
§
§
803.50
8
0
3
.
5
0
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
as
a
s
well
w
e
l
l
as
a
s
supplemental
s
u
p
p
l
e
m
e
n
t
a
l
or
o
r
followup
f
o
l
l
o
w
u
p
reports
r
e
p
o
r
t
s
to
t
o
such
s
u
c
h
a
a
report
r
e
p
o
r
t
as
a
s
described
d
e
s
c
r
i
b
e
d
in
i
n
§
§
803.56
8
0
3
.
5
6
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
New
N
e
w
drug
d
r
u
g
application
a
p
p
l
i
c
a
t
i
o
n
(NDA)
(
N
D
A
)
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
‘‘application’’
‘
‘
a
p
p
l
i
c
a
t
i
o
n
’
’
in
i
n
§
§
314.3(b)
3
1
4
.
3
(
b
)
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Premarket
P
r
e
m
a
r
k
e
t
approval
a
p
p
r
o
v
a
l
application
a
p
p
l
i
c
a
t
i
o
n
(PMA)
(
P
M
A
)
has
h
a
s
the
t
h
e
meaning
m
e
a
n
i
n
g
given
g
i
v
e
n
the
t
h
e
term
t
e
r
m
in
i
n
§
§
814.3
8
1
4
.
3
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Premarket
P
r
e
m
a
r
k
e
t
notification
n
o
t
i
f
i
c
a
t
i
o
n
submission
s
u
b
m
i
s
s
i
o
n
is
i
s
a
a
submission
s
u
b
m
i
s
s
i
o
n
as
a
s
described
d
e
s
c
r
i
b
e
d
in
i
n
§
§
807.87
8
0
7
.
8
7
of
o
f
this
t
h
i
s
chapter.
c
h
a
p
t
e
r
.
Product
P
r
o
d
u
c
t
Development
D
e
v
e
l
o
p
m
e
n
t
Protocol
P
r
o
t
o
c
o
l
(PDP)
(
P
D
P
)
is
i
s
a
a
submission
s
u
b
m
i
s
s
i
o
n
as
a
s
set
s
e
t
forth
f
o
r
t
h
in
i
n
section
s
e
c
t
i
o
n
515(f)
5
1
5
(
f
)
of
o
f
the
t
h
e
Federal
F
e
d
e
r
a
l
Food,
F
o
o
d
,
Drug,
D
r
u
g
,
and
a
n
d
Cosmetic
C
o
s
m
e
t
i
c
Act.
A
c
t
.
181
1
8
1
§
§
4.102
4
.
1
0
2
What
W
h
a
t
reports
r
e
p
o
r
t
s
must
m
u
s
t
you
y
o
u
submit
s
u
b
m
i
t
to
t
o
FDA
F
D
A
for
f
o
r
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
prod-
p
r
o
d
-
uct
u
c
t
or
o
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part?
p
a
r
t
?
(a)
(
a
)
In
I
n
general.
g
e
n
e
r
a
l
.
If
I
f
you
y
o
u
are
a
r
e
a
a
con-
c
o
n
-
stituent
s
t
i
t
u
e
n
t
part
p
a
r
t
applicant,
a
p
p
l
i
c
a
n
t
,
the
t
h
e
reporting
r
e
p
o
r
t
i
n
g
requirements
r
e
q
u
i
r
e
m
e
n
t
s
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
you
y
o
u
that
t
h
a
t
are
a
r
e
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
this
t
h
i
s
section
s
e
c
t
i
o
n
apply
a
p
p
l
y
to
t
o
your
y
o
u
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part,
p
a
r
t
,
and
a
n
d
if
i
f
you
y
o
u
are
a
r
e
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicant,
a
p
p
l
i
c
a
n
t
,
the
t
h
e
re-
r
e
-
porting
p
o
r
t
i
n
g
requirements
r
e
q
u
i
r
e
m
e
n
t
s
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
you
y
o
u
that
t
h
a
t
are
a
r
e
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
this
t
h
i
s
section
s
e
c
t
i
o
n
apply
a
p
p
l
y
to
t
o
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
as
a
s
a
a
whole.
w
h
o
l
e
.
(b)
(
b
)
Reporting
R
e
p
o
r
t
i
n
g
requirements
r
e
q
u
i
r
e
m
e
n
t
s
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
both
b
o
t
h
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicants
a
p
p
l
i
c
a
n
t
s
and
a
n
d
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
applicants.
a
p
p
l
i
c
a
n
t
s
.
If
I
f
you
y
o
u
are
a
r
e
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicant
a
p
p
l
i
c
a
n
t
or
o
r
con-
c
o
n
-
stituent
s
t
i
t
u
e
n
t
part
p
a
r
t
applicant,
a
p
p
l
i
c
a
n
t
,
you
y
o
u
must
m
u
s
t
com-
c
o
m
-
ply
p
l
y
with
w
i
t
h
the
t
h
e
reporting
r
e
p
o
r
t
i
n
g
requirements
r
e
q
u
i
r
e
m
e
n
t
s
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
paragraphs
p
a
r
a
g
r
a
p
h
s
(b)(1),
(
b
)
(
1
)
,
(b)(2),
(
b
)
(
2
)
,
or
o
r
(b)(3)
(
b
)
(
3
)
of
o
f
this
t
h
i
s
section
s
e
c
t
i
o
n
for
f
o
r
your
y
o
u
r
product
p
r
o
d
u
c
t
based
b
a
s
e
d
on
o
n
its
i
t
s
application
a
p
p
l
i
c
a
t
i
o
n
type.
t
y
p
e
.
If
I
f
you
y
o
u
are
a
r
e
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicant,
a
p
p
l
i
c
a
n
t
,
you
y
o
u
are
a
r
e
required
r
e
q
u
i
r
e
d
to
t
o
submit
s
u
b
m
i
t
a
a
report
r
e
p
o
r
t
as
a
s
specified
s
p
e
c
i
f
i
e
d
in
i
n
this
t
h
i
s
paragraph
p
a
r
a
g
r
a
p
h
unless
u
n
l
e
s
s
you
y
o
u
have
h
a
v
e
already
a
l
r
e
a
d
y
submitted
s
u
b
m
i
t
t
e
d
a
a
report
r
e
p
o
r
t
in
i
n
ac-
a
c
-
cordance
c
o
r
d
a
n
c
e
with
w
i
t
h
paragraph
p
a
r
a
g
r
a
p
h
(c)
(
c
)
of
o
f
this
t
h
i
s
sec-
s
e
c
-
tion
t
i
o
n
for
f
o
r
the
t
h
e
same
s
a
m
e
event
e
v
e
n
t
that:
t
h
a
t
:
Includes
I
n
c
l
u
d
e
s
the
t
h
e
information
i
n
f
o
r
m
a
t
i
o
n
required
r
e
q
u
i
r
e
d
under
u
n
d
e
r
the
t
h
e
ap-
a
p
-
plicable
p
l
i
c
a
b
l
e
regulations
r
e
g
u
l
a
t
i
o
n
s
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
this
t
h
i
s
paragraph,
p
a
r
a
g
r
a
p
h
,
is
i
s
required
r
e
q
u
i
r
e
d
to
t
o
be
b
e
submitted
s
u
b
m
i
t
t
e
d
in
i
n
the
t
h
e
same
s
a
m
e
manner
m
a
n
n
e
r
under
u
n
d
e
r
§
§
4.104,
4
.
1
0
4
,
and
a
n
d
meets
m
e
e
t
s
the
t
h
e
deadlines
d
e
a
d
l
i
n
e
s
under
u
n
d
e
r
the
t
h
e
applica-
a
p
p
l
i
c
a
-
ble
b
l
e
regulations
r
e
g
u
l
a
t
i
o
n
s
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
this
t
h
i
s
para-
p
a
r
a
-
graph.
g
r
a
p
h
.
-
If
I
f
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
or
o
r
de-
d
e
-
vice
v
i
c
e
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
received
r
e
c
e
i
v
e
d
mar-
m
a
r
-
keting
k
e
t
i
n
g
authorization
a
u
t
h
o
r
i
z
a
t
i
o
n
under
u
n
d
e
r
a
a
device
d
e
v
i
c
e
ap-
a
p
-
plication,
p
l
i
c
a
t
i
o
n
,
you
y
o
u
must
m
u
s
t
comply
c
o
m
p
l
y
with
w
i
t
h
the
t
h
e
requirements
r
e
q
u
i
r
e
m
e
n
t
s
for
f
o
r
postmarketing
p
o
s
t
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reporting
r
e
p
o
r
t
i
n
g
described
d
e
s
c
r
i
b
e
d
in
i
n
parts
p
a
r
t
s
803
8
0
3
and
a
n
d
806
8
0
6
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
with
w
i
t
h
respect
r
e
s
p
e
c
t
to
t
o
your
y
o
u
r
product.
p
r
o
d
u
c
t
.
-
If
I
f
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
or
o
r
drug
d
r
u
g
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
received
r
e
c
e
i
v
e
d
mar-
m
a
r
-
keting
k
e
t
i
n
g
authorization
a
u
t
h
o
r
i
z
a
t
i
o
n
under
u
n
d
e
r
an
a
n
NDA
N
D
A
or
o
r
ANDA,
A
N
D
A
,
you
y
o
u
must
m
u
s
t
comply
c
o
m
p
l
y
with
w
i
t
h
the
t
h
e
re-
r
e
-
quirements
q
u
i
r
e
m
e
n
t
s
for
f
o
r
postmarketing
p
o
s
t
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reporting
r
e
p
o
r
t
i
n
g
described
d
e
s
c
r
i
b
e
d
in
i
n
part
p
a
r
t
314
3
1
4
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
with
w
i
t
h
respect
r
e
s
p
e
c
t
to
t
o
your
y
o
u
r
product.
p
r
o
d
u
c
t
.
-
If
I
f
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
or
o
r
bi-
b
i
-
ological
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
re-
r
e
-
ceived
c
e
i
v
e
d
marketing
m
a
r
k
e
t
i
n
g
authorization
a
u
t
h
o
r
i
z
a
t
i
o
n
under
u
n
d
e
r
a
a
BLA,
B
L
A
,
you
y
o
u
must
m
u
s
t
comply
c
o
m
p
l
y
with
w
i
t
h
the
t
h
e
re-
r
e
-
quirements
q
u
i
r
e
m
e
n
t
s
for
f
o
r
postmarketing
p
o
s
t
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reporting
r
e
p
o
r
t
i
n
g
described
d
e
s
c
r
i
b
e
d
in
i
n
parts
p
a
r
t
s
600
6
0
0
and
a
n
d
606
6
0
6
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
with
w
i
t
h
respect
r
e
s
p
e
c
t
to
t
o
your
y
o
u
r
product.
p
r
o
d
u
c
t
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§
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1
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2
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CFR
C
F
R
Ch.
C
h
.
I
I
(4–1–25
(
4
–
1
–
2
5
Edition)
E
d
i
t
i
o
n
)
jspears
j
s
p
e
a
r
s
on
o
n
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S
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1
2
1
T
N
2
3
P
R
O
D
with
w
i
t
h
CFR
C
F
R
(c)
(
c
)
Reporting
R
e
p
o
r
t
i
n
g
requirements
r
e
q
u
i
r
e
m
e
n
t
s
applicable
a
p
p
l
i
c
a
b
l
e
only
o
n
l
y
to
t
o
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicants.
a
p
p
l
i
c
a
n
t
s
.
If
I
f
you
y
o
u
are
a
r
e
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
appli-
a
p
p
l
i
-
cant,
c
a
n
t
,
in
i
n
addition
a
d
d
i
t
i
o
n
to
t
o
compliance
c
o
m
p
l
i
a
n
c
e
with
w
i
t
h
paragraph
p
a
r
a
g
r
a
p
h
(a)
(
a
)
of
o
f
this
t
h
i
s
section,
s
e
c
t
i
o
n
,
you
y
o
u
must
m
u
s
t
also
a
l
s
o
comply
c
o
m
p
l
y
with
w
i
t
h
the
t
h
e
reporting
r
e
p
o
r
t
i
n
g
require-
r
e
q
u
i
r
e
-
ments
m
e
n
t
s
identified
i
d
e
n
t
i
f
i
e
d
under
u
n
d
e
r
this
t
h
i
s
paragraph
p
a
r
a
g
r
a
p
h
as
a
s
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
your
y
o
u
r
product
p
r
o
d
u
c
t
based
b
a
s
e
d
on
o
n
its
i
t
s
constituent
c
o
n
s
t
i
t
u
e
n
t
parts.
p
a
r
t
s
.
If
I
f
you
y
o
u
are
a
r
e
a
a
com-
c
o
m
-
bination
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicant,
a
p
p
l
i
c
a
n
t
,
you
y
o
u
are
a
r
e
re-
r
e
-
quired
q
u
i
r
e
d
to
t
o
submit
s
u
b
m
i
t
a
a
report
r
e
p
o
r
t
as
a
s
specified
s
p
e
c
i
f
i
e
d
in
i
n
this
t
h
i
s
paragraph
p
a
r
a
g
r
a
p
h
unless
u
n
l
e
s
s
you
y
o
u
have
h
a
v
e
al-
a
l
-
ready
r
e
a
d
y
submitted
s
u
b
m
i
t
t
e
d
a
a
report
r
e
p
o
r
t
in
i
n
accordance
a
c
c
o
r
d
a
n
c
e
with
w
i
t
h
paragraph
p
a
r
a
g
r
a
p
h
(b)
(
b
)
of
o
f
this
t
h
i
s
section
s
e
c
t
i
o
n
for
f
o
r
the
t
h
e
same
s
a
m
e
event
e
v
e
n
t
that:
t
h
a
t
:
Includes
I
n
c
l
u
d
e
s
the
t
h
e
in-
i
n
-
formation
f
o
r
m
a
t
i
o
n
required
r
e
q
u
i
r
e
d
under
u
n
d
e
r
the
t
h
e
applica-
a
p
p
l
i
c
a
-
ble
b
l
e
regulations
r
e
g
u
l
a
t
i
o
n
s
for
f
o
r
the
t
h
e
report
r
e
p
o
r
t
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
this
t
h
i
s
paragraph;
p
a
r
a
g
r
a
p
h
;
is
i
s
required
r
e
q
u
i
r
e
d
to
t
o
be
b
e
sub-
s
u
b
-
mitted
m
i
t
t
e
d
in
i
n
the
t
h
e
same
s
a
m
e
manner
m
a
n
n
e
r
under
u
n
d
e
r
§
§
4.104
4
.
1
0
4
of
o
f
this
t
h
i
s
chapter;
c
h
a
p
t
e
r
;
and,
a
n
d
,
unless
u
n
l
e
s
s
oth-
o
t
h
-
erwise
e
r
w
i
s
e
specified
s
p
e
c
i
f
i
e
d
in
i
n
this
t
h
i
s
paragraph,
p
a
r
a
g
r
a
p
h
,
meets
m
e
e
t
s
the
t
h
e
deadlines
d
e
a
d
l
i
n
e
s
under
u
n
d
e
r
the
t
h
e
applica-
a
p
p
l
i
c
a
-
ble
b
l
e
regulations
r
e
g
u
l
a
t
i
o
n
s
for
f
o
r
the
t
h
e
report
r
e
p
o
r
t
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
this
t
h
i
s
paragraph.
p
a
r
a
g
r
a
p
h
.
-
If
I
f
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
con-
c
o
n
-
tains
t
a
i
n
s
a
a
device
d
e
v
i
c
e
constituent
c
o
n
s
t
i
t
u
e
n
t
part,
p
a
r
t
,
you
y
o
u
must
m
u
s
t
submit:
s
u
b
m
i
t
:
(i)
(
i
)
Five-day
F
i
v
e
-
d
a
y
reports;
r
e
p
o
r
t
s
;
(ii)
(
i
i
)
Malfunction
M
a
l
f
u
n
c
t
i
o
n
reports;
r
e
p
o
r
t
s
;
and
a
n
d
(iii)
(
i
i
i
)
Correction
C
o
r
r
e
c
t
i
o
n
or
o
r
removal
r
e
m
o
v
a
l
reports,
r
e
p
o
r
t
s
,
and
a
n
d
maintain
m
a
i
n
t
a
i
n
records
r
e
c
o
r
d
s
as
a
s
described
d
e
s
c
r
i
b
e
d
in
i
n
§
§
806.20
8
0
6
.
2
0
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
for
f
o
r
corrections
c
o
r
r
e
c
t
i
o
n
s
and
a
n
d
removals
r
e
m
o
v
a
l
s
not
n
o
t
required
r
e
q
u
i
r
e
d
to
t
o
be
b
e
re-
r
e
-
ported.
p
o
r
t
e
d
.
-
If
I
f
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
con-
c
o
n
-
tains
t
a
i
n
s
a
a
drug
d
r
u
g
constituent
c
o
n
s
t
i
t
u
e
n
t
part,
p
a
r
t
,
you
y
o
u
must
m
u
s
t
submit:
s
u
b
m
i
t
:
(i)
(
i
)
Field
F
i
e
l
d
alert
a
l
e
r
t
reports;
r
e
p
o
r
t
s
;
and
a
n
d
(ii)
(
i
i
)
Fifteen-day
F
i
f
t
e
e
n
-
d
a
y
reports
r
e
p
o
r
t
s
as
a
s
described
d
e
s
c
r
i
b
e
d
in
i
n
§
§
314.80
3
1
4
.
8
0
of
o
f
this
t
h
i
s
chapter,
c
h
a
p
t
e
r
,
which
w
h
i
c
h
must
m
u
s
t
be
b
e
submitted
s
u
b
m
i
t
t
e
d
within
w
i
t
h
i
n
30
3
0
calendar
c
a
l
e
n
d
a
r
days
d
a
y
s
instead
i
n
s
t
e
a
d
of
o
f
15
1
5
calendar
c
a
l
e
n
d
a
r
days
d
a
y
s
if
i
f
your
y
o
u
r
com-
c
o
m
-
bination
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
received
r
e
c
e
i
v
e
d
marketing
m
a
r
k
e
t
i
n
g
authorization
a
u
t
h
o
r
i
z
a
t
i
o
n
under
u
n
d
e
r
a
a
device
d
e
v
i
c
e
applica-
a
p
p
l
i
c
a
-
tion.
t
i
o
n
.
-
If
I
f
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
con-
c
o
n
-
tains
t
a
i
n
s
a
a
biological
b
i
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
constituent
c
o
n
s
t
i
t
u
e
n
t
part,
p
a
r
t
,
you
y
o
u
must
m
u
s
t
submit:
s
u
b
m
i
t
:
(i)
(
i
)
Biological
B
i
o
l
o
g
i
c
a
l
product
p
r
o
d
u
c
t
deviation
d
e
v
i
a
t
i
o
n
re-
r
e
-
ports;
p
o
r
t
s
;
and
a
n
d
(ii)
(
i
i
)
Fifteen-day
F
i
f
t
e
e
n
-
d
a
y
reports
r
e
p
o
r
t
s
as
a
s
described
d
e
s
c
r
i
b
e
d
in
i
n
§
§
600.80
6
0
0
.
8
0
of
o
f
this
t
h
i
s
chapter,
c
h
a
p
t
e
r
,
which
w
h
i
c
h
must
m
u
s
t
be
b
e
submitted
s
u
b
m
i
t
t
e
d
within
w
i
t
h
i
n
30
3
0
calendar
c
a
l
e
n
d
a
r
days
d
a
y
s
instead
i
n
s
t
e
a
d
of
o
f
15
1
5
calendar
c
a
l
e
n
d
a
r
days
d
a
y
s
if
i
f
your
y
o
u
r
com-
c
o
m
-
bination
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
received
r
e
c
e
i
v
e
d
marketing
m
a
r
k
e
t
i
n
g
authorization
a
u
t
h
o
r
i
z
a
t
i
o
n
under
u
n
d
e
r
a
a
device
d
e
v
i
c
e
applica-
a
p
p
l
i
c
a
-
tion.
t
i
o
n
.
(d)
(
d
)
Other
O
t
h
e
r
reporting
r
e
p
o
r
t
i
n
g
requirements
r
e
q
u
i
r
e
m
e
n
t
s
for
f
o
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicants.
a
p
p
l
i
c
a
n
t
s
.
(1)
(
1
)
If
I
f
182
1
8
2
you
y
o
u
are
a
r
e
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
appli-
a
p
p
l
i
-
cant
c
a
n
t
for
f
o
r
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
that
t
h
a
t
contains
c
o
n
t
a
i
n
s
a
a
device
d
e
v
i
c
e
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
and
a
n
d
that
t
h
a
t
received
r
e
c
e
i
v
e
d
marketing
m
a
r
k
e
t
i
n
g
authorization
a
u
t
h
o
r
i
z
a
t
i
o
n
under
u
n
d
e
r
an
a
n
NDA,
N
D
A
,
ANDA,
A
N
D
A
,
or
o
r
BLA,
B
L
A
,
in
i
n
addi-
a
d
d
i
-
tion
t
i
o
n
to
t
o
the
t
h
e
information
i
n
f
o
r
m
a
t
i
o
n
otherwise
o
t
h
e
r
w
i
s
e
re-
r
e
-
quired
q
u
i
r
e
d
in
i
n
the
t
h
e
periodic
p
e
r
i
o
d
i
c
safety
s
a
f
e
t
y
reports
r
e
p
o
r
t
s
you
y
o
u
submit
s
u
b
m
i
t
under
u
n
d
e
r
§
§
314.80
3
1
4
.
8
0
or
o
r
§
§
600.80
6
0
0
.
8
0
of
o
f
this
t
h
i
s
chapter,
c
h
a
p
t
e
r
,
your
y
o
u
r
periodic
p
e
r
i
o
d
i
c
safety
s
a
f
e
t
y
re-
r
e
-
ports
p
o
r
t
s
must
m
u
s
t
also
a
l
s
o
include
i
n
c
l
u
d
e
a
a
summary
s
u
m
m
a
r
y
and
a
n
d
analysis
a
n
a
l
y
s
i
s
of
o
f
the
t
h
e
reports
r
e
p
o
r
t
s
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
paragraphs
p
a
r
a
g
r
a
p
h
s
(c)(1)(i)
(
c
)
(
1
)
(
i
)
and
a
n
d
(ii)
(
i
i
)
of
o
f
this
t
h
i
s
sec-
s
e
c
-
tion
t
i
o
n
that
t
h
a
t
were
w
e
r
e
submitted
s
u
b
m
i
t
t
e
d
during
d
u
r
i
n
g
the
t
h
e
re-
r
e
-
port
p
o
r
t
interval.
i
n
t
e
r
v
a
l
.
-
If
I
f
you
y
o
u
are
a
r
e
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
prod-
p
r
o
d
-
uct
u
c
t
applicant
a
p
p
l
i
c
a
n
t
for
f
o
r
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
prod-
p
r
o
d
-
uct
u
c
t
that
t
h
a
t
received
r
e
c
e
i
v
e
d
marketing
m
a
r
k
e
t
i
n
g
authoriza-
a
u
t
h
o
r
i
z
a
-
tion
t
i
o
n
under
u
n
d
e
r
a
a
device
d
e
v
i
c
e
application,
a
p
p
l
i
c
a
t
i
o
n
,
in
i
n
ad-
a
d
-
dition
d
i
t
i
o
n
to
t
o
the
t
h
e
reports
r
e
p
o
r
t
s
required
r
e
q
u
i
r
e
d
under
u
n
d
e
r
paragraphs
p
a
r
a
g
r
a
p
h
s
(b)
(
b
)
and
a
n
d
(c)
(
c
)
of
o
f
this
t
h
i
s
section,
s
e
c
t
i
o
n
,
you
y
o
u
must
m
u
s
t
submit
s
u
b
m
i
t
reports
r
e
p
o
r
t
s
regarding
r
e
g
a
r
d
i
n
g
postmarketing
p
o
s
t
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
events
e
v
e
n
t
s
if
i
f
notified
n
o
t
i
f
i
e
d
by
b
y
the
t
h
e
Agency
A
g
e
n
c
y
in
i
n
writing
w
r
i
t
i
n
g
that
t
h
a
t
the
t
h
e
Agency
A
g
e
n
c
y
requires
r
e
q
u
i
r
e
s
additional
a
d
d
i
t
i
o
n
a
l
informa-
i
n
f
o
r
m
a
-
tion.
t
i
o
n
.
We
W
e
will
w
i
l
l
specify
s
p
e
c
i
f
y
what
w
h
a
t
safety
s
a
f
e
t
y
infor-
i
n
f
o
r
-
mation
m
a
t
i
o
n
is
i
s
needed
n
e
e
d
e
d
and
a
n
d
will
w
i
l
l
require
r
e
q
u
i
r
e
such
s
u
c
h
information
i
n
f
o
r
m
a
t
i
o
n
if
i
f
we
w
e
determine
d
e
t
e
r
m
i
n
e
that
t
h
a
t
pro-
p
r
o
-
tection
t
e
c
t
i
o
n
of
o
f
the
t
h
e
public
p
u
b
l
i
c
health
h
e
a
l
t
h
requires
r
e
q
u
i
r
e
s
additional
a
d
d
i
t
i
o
n
a
l
or
o
r
clarifying
c
l
a
r
i
f
y
i
n
g
safety
s
a
f
e
t
y
informa-
i
n
f
o
r
m
a
-
tion
t
i
o
n
for
f
o
r
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product.
p
r
o
d
u
c
t
.
In
I
n
any
a
n
y
request
r
e
q
u
e
s
t
under
u
n
d
e
r
this
t
h
i
s
section,
s
e
c
t
i
o
n
,
we
w
e
will
w
i
l
l
state
s
t
a
t
e
the
t
h
e
reason
r
e
a
s
o
n
or
o
r
purpose
p
u
r
p
o
s
e
for
f
o
r
the
t
h
e
safety
s
a
f
e
t
y
information
i
n
f
o
r
m
a
t
i
o
n
request,
r
e
q
u
e
s
t
,
specify
s
p
e
c
i
f
y
the
t
h
e
due
d
u
e
date
d
a
t
e
for
f
o
r
submitting
s
u
b
m
i
t
t
i
n
g
the
t
h
e
informa-
i
n
f
o
r
m
a
-
tion,
t
i
o
n
,
and
a
n
d
clearly
c
l
e
a
r
l
y
identify
i
d
e
n
t
i
f
y
the
t
h
e
reported
r
e
p
o
r
t
e
d
event(s)
e
v
e
n
t
(
s
)
related
r
e
l
a
t
e
d
to
t
o
our
o
u
r
request.
r
e
q
u
e
s
t
.
§
§
4.103
4
.
1
0
3
What
W
h
a
t
information
i
n
f
o
r
m
a
t
i
o
n
must
m
u
s
t
you
y
o
u
share
s
h
a
r
e
with
w
i
t
h
other
o
t
h
e
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
applicants
a
p
p
l
i
c
a
n
t
s
for
f
o
r
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product?
p
r
o
d
u
c
t
?
(a)
(
a
)
When
W
h
e
n
you
y
o
u
receive
r
e
c
e
i
v
e
information
i
n
f
o
r
m
a
t
i
o
n
re-
r
e
-
garding
g
a
r
d
i
n
g
an
a
n
event
e
v
e
n
t
that
t
h
a
t
involves
i
n
v
o
l
v
e
s
a
a
death
d
e
a
t
h
or
o
r
serious
s
e
r
i
o
u
s
injury
i
n
j
u
r
y
as
a
s
described
d
e
s
c
r
i
b
e
d
in
i
n
§
§
803.3
8
0
3
.
3
of
o
f
this
t
h
i
s
chapter,
c
h
a
p
t
e
r
,
or
o
r
an
a
n
adverse
a
d
v
e
r
s
e
experi-
e
x
p
e
r
i
-
ence
e
n
c
e
as
a
s
described
d
e
s
c
r
i
b
e
d
in
i
n
§
§
314.80(a)
3
1
4
.
8
0
(
a
)
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
or
o
r
§
§
600.80(a)
6
0
0
.
8
0
(
a
)
of
o
f
this
t
h
i
s
chapter,
c
h
a
p
t
e
r
,
as-
a
s
-
sociated
s
o
c
i
a
t
e
d
with
w
i
t
h
the
t
h
e
use
u
s
e
of
o
f
the
t
h
e
combina-
c
o
m
b
i
n
a
-
tion
t
i
o
n
product,
p
r
o
d
u
c
t
,
you
y
o
u
must
m
u
s
t
provide
p
r
o
v
i
d
e
the
t
h
e
in-
i
n
-
formation
f
o
r
m
a
t
i
o
n
to
t
o
the
t
h
e
other
o
t
h
e
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
applicant(s)
a
p
p
l
i
c
a
n
t
(
s
)
for
f
o
r
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
no
n
o
later
l
a
t
e
r
than
t
h
a
n
5
5
calendar
c
a
l
e
n
d
a
r
days
d
a
y
s
of
o
f
your
y
o
u
r
receipt
r
e
c
e
i
p
t
of
o
f
the
t
h
e
information.
i
n
f
o
r
m
a
t
i
o
n
.
(b)
(
b
)
With
W
i
t
h
regard
r
e
g
a
r
d
to
t
o
information
i
n
f
o
r
m
a
t
i
o
n
you
y
o
u
must
m
u
s
t
provide
p
r
o
v
i
d
e
to
t
o
the
t
h
e
other
o
t
h
e
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
applicant(s)
a
p
p
l
i
c
a
n
t
(
s
)
for
f
o
r
the
t
h
e
combination
c
o
m
b
i
n
a
t
i
o
n
product,
p
r
o
d
u
c
t
,
you
y
o
u
must
m
u
s
t
maintain
m
a
i
n
t
a
i
n
records
r
e
c
o
r
d
s
that
t
h
a
t
include:
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c
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Food
F
o
o
d
and
a
n
d
Drug
D
r
u
g
Administration,
A
d
m
i
n
i
s
t
r
a
t
i
o
n
,
HHS
H
H
S
§
§
5.1100
5
.
1
1
0
0
-
A
A
copy
c
o
p
y
of
o
f
the
t
h
e
information
i
n
f
o
r
m
a
t
i
o
n
you
y
o
u
provided,
p
r
o
v
i
d
e
d
,
-
The
T
h
e
date
d
a
t
e
the
t
h
e
information
i
n
f
o
r
m
a
t
i
o
n
was
w
a
s
re-
r
e
-
ceived
c
e
i
v
e
d
by
b
y
you,
y
o
u
,
-
The
T
h
e
date
d
a
t
e
the
t
h
e
information
i
n
f
o
r
m
a
t
i
o
n
was
w
a
s
pro-
p
r
o
-
vided
v
i
d
e
d
to
t
o
the
t
h
e
other
o
t
h
e
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
ap-
a
p
-
plicant(s),
p
l
i
c
a
n
t
(
s
)
,
and
a
n
d
-
The
T
h
e
name
n
a
m
e
and
a
n
d
address
a
d
d
r
e
s
s
of
o
f
the
t
h
e
other
o
t
h
e
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
applicant(s)
a
p
p
l
i
c
a
n
t
(
s
)
to
t
o
whom
w
h
o
m
you
y
o
u
provided
p
r
o
v
i
d
e
d
the
t
h
e
information.
i
n
f
o
r
m
a
t
i
o
n
.
regulations
r
e
g
u
l
a
t
i
o
n
s
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
your
y
o
u
r
product
p
r
o
d
u
c
t
under
u
n
d
e
r
§
§
4.102(b).
4
.
1
0
2
(
b
)
.
(b)
(
b
)
If
I
f
you
y
o
u
are
a
r
e
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicant,
a
p
p
l
i
c
a
n
t
,
you
y
o
u
must
m
u
s
t
maintain
m
a
i
n
t
a
i
n
records
r
e
c
o
r
d
s
in
i
n
accordance
a
c
c
o
r
d
a
n
c
e
with
w
i
t
h
the
t
h
e
longest
l
o
n
g
e
s
t
time
t
i
m
e
pe-
p
e
-
riod
r
i
o
d
required
r
e
q
u
i
r
e
d
for
f
o
r
records
r
e
c
o
r
d
s
under
u
n
d
e
r
the
t
h
e
reg-
r
e
g
-
ulations
u
l
a
t
i
o
n
s
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
your
y
o
u
r
product
p
r
o
d
u
c
t
under
u
n
d
e
r
§
§
4.102.
4
.
1
0
2
.
PART
P
A
R
T
5—ORGANIZATION
5
—
O
R
G
A
N
I
Z
A
T
I
O
N
jspears
j
s
p
e
a
r
s
on
o
n
DSK121TN23PROD
D
S
K
1
2
1
T
N
2
3
P
R
O
D
with
w
i
t
h
CFR
C
F
R
§
§
4.104
4
.
1
0
4
How
H
o
w
and
a
n
d
where
w
h
e
r
e
must
m
u
s
t
you
y
o
u
sub-
s
u
b
-
mit
m
i
t
postmarketing
p
o
s
t
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reports
r
e
p
o
r
t
s
for
f
o
r
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
or
o
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part?
p
a
r
t
?
(a)
(
a
)
If
I
f
you
y
o
u
are
a
r
e
a
a
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
ap-
a
p
-
plicant,
p
l
i
c
a
n
t
,
you
y
o
u
must
m
u
s
t
submit
s
u
b
m
i
t
post-
p
o
s
t
-
marketing
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reports
r
e
p
o
r
t
s
in
i
n
accordance
a
c
c
o
r
d
a
n
c
e
with
w
i
t
h
the
t
h
e
regulations
r
e
g
u
l
a
t
i
o
n
s
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
§
§
4.102(b)
4
.
1
0
2
(
b
)
that
t
h
a
t
are
a
r
e
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
your
y
o
u
r
product
p
r
o
d
u
c
t
based
b
a
s
e
d
on
o
n
its
i
t
s
application
a
p
p
l
i
c
a
t
i
o
n
type.
t
y
p
e
.
(b)
(
b
)
If
I
f
you
y
o
u
are
a
r
e
a
a
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
applicant,
a
p
p
l
i
c
a
n
t
,
you
y
o
u
must
m
u
s
t
submit
s
u
b
m
i
t
post-
p
o
s
t
-
marketing
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reports
r
e
p
o
r
t
s
required
r
e
q
u
i
r
e
d
under
u
n
d
e
r
§
§
4.102
4
.
1
0
2
in
i
n
the
t
h
e
manner
m
a
n
n
e
r
specified
s
p
e
c
i
f
i
e
d
in
i
n
the
t
h
e
regulation
r
e
g
u
l
a
t
i
o
n
applicable
a
p
p
l
i
c
a
b
l
e
to
t
o
the
t
h
e
type
t
y
p
e
of
o
f
report,
r
e
p
o
r
t
,
with
w
i
t
h
the
t
h
e
following
f
o
l
l
o
w
i
n
g
exceptions:
e
x
c
e
p
t
i
o
n
s
:
-
You
Y
o
u
must
m
u
s
t
submit
s
u
b
m
i
t
the
t
h
e
post-
p
o
s
t
-
marketing
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reports
r
e
p
o
r
t
s
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
§
§
4.102(c)(1)(i)
4
.
1
0
2
(
c
)
(
1
)
(
i
)
and
a
n
d
(ii)
(
i
i
)
in
i
n
accordance
a
c
c
o
r
d
a
n
c
e
with
w
i
t
h
§
§
314.80(g)
3
1
4
.
8
0
(
g
)
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
if
i
f
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
received
r
e
c
e
i
v
e
d
mar-
m
a
r
-
keting
k
e
t
i
n
g
authorization
a
u
t
h
o
r
i
z
a
t
i
o
n
under
u
n
d
e
r
an
a
n
NDA
N
D
A
or
o
r
ANDA
A
N
D
A
or
o
r
in
i
n
accordance
a
c
c
o
r
d
a
n
c
e
with
w
i
t
h
§
§
600.80(h)
6
0
0
.
8
0
(
h
)
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
if
i
f
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
received
r
e
c
e
i
v
e
d
marketing
m
a
r
k
e
t
i
n
g
authoriza-
a
u
t
h
o
r
i
z
a
-
tion
t
i
o
n
under
u
n
d
e
r
a
a
BLA.
B
L
A
.
-
You
Y
o
u
must
m
u
s
t
submit
s
u
b
m
i
t
the
t
h
e
post-
p
o
s
t
-
marketing
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reports
r
e
p
o
r
t
s
identified
i
d
e
n
t
i
f
i
e
d
in
i
n
§
§
4.102(c)(2)(ii)
4
.
1
0
2
(
c
)
(
2
)
(
i
i
)
and
a
n
d
(c)(3)(ii)
(
c
)
(
3
)
(
i
i
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in
i
n
accord-
a
c
c
o
r
d
-
ance
a
n
c
e
with
w
i
t
h
§
§
803.12(a)
8
0
3
.
1
2
(
a
)
of
o
f
this
t
h
i
s
chapter
c
h
a
p
t
e
r
if
i
f
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
received
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e
c
e
i
v
e
d
marketing
m
a
r
k
e
t
i
n
g
authorization
a
u
t
h
o
r
i
z
a
t
i
o
n
under
u
n
d
e
r
a
a
de-
d
e
-
vice
v
i
c
e
application.
a
p
p
l
i
c
a
t
i
o
n
.
§
§
4.105
4
.
1
0
5
What
W
h
a
t
are
a
r
e
the
t
h
e
postmarketing
p
o
s
t
m
a
r
k
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t
i
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g
safety
s
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f
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t
y
reporting
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e
p
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r
t
i
n
g
recordkeeping
r
e
c
o
r
d
k
e
e
p
i
n
g
re-
r
e
-
quirements
q
u
i
r
e
m
e
n
t
s
for
f
o
r
your
y
o
u
r
combination
c
o
m
b
i
n
a
t
i
o
n
product
p
r
o
d
u
c
t
or
o
r
constituent
c
o
n
s
t
i
t
u
e
n
t
part?
p
a
r
t
?
(a)
(
a
)
If
I
f
you
y
o
u
are
a
r
e
a
a
constituent
c
o
n
s
t
i
t
u
e
n
t
part
p
a
r
t
ap-
a
p
-
plicant:
p
l
i
c
a
n
t
:
-
You
Y
o
u
must
m
u
s
t
maintain
m
a
i
n
t
a
i
n
records
r
e
c
o
r
d
s
in
i
n
ac-
a
c
-
cordance
c
o
r
d
a
n
c
e
with
w
i
t
h
the
t
h
e
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r
e
c
o
r
d
k
e
e
p
i
n
g
re-
r
e
-
quirements
q
u
i
r
e
m
e
n
t
s
in
i
n
the
t
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e
applicable
a
p
p
l
i
c
a
b
l
e
regula-
r
e
g
u
l
a
-
tion(s)
t
i
o
n
(
s
)
described
d
e
s
c
r
i
b
e
d
in
i
n
§
§
4.102(b).
4
.
1
0
2
(
b
)
.
-
You
Y
o
u
must
m
u
s
t
maintain
m
a
i
n
t
a
i
n
records
r
e
c
o
r
d
s
re-
r
e
-
quired
q
u
i
r
e
d
under
u
n
d
e
r
§
§
4.103(b)
4
.
1
0
3
(
b
)
for
f
o
r
the
t
h
e
longest
l
o
n
g
e
s
t
time
t
i
m
e
period
p
e
r
i
o
d
required
r
e
q
u
i
r
e
d
for
f
o
r
records
r
e
c
o
r
d
s
under
u
n
d
e
r
the
t
h
e
postmarketing
p
o
s
t
m
a
r
k
e
t
i
n
g
safety
s
a
f
e
t
y
reporting
r
e
p
o
r
t
i
n
g
183
1
8
3
Subparts
S
u
b
p
a
r
t
s
A–L
A
–
L
[Reserved]
[
R
e
s
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v
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d
]
Subpart
S
u
b
p
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M
—
O
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n
i
z
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i
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Sec.
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c
.
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5
.
1
1
0
0
Headquarters.
H
e
a
d
q
u
a
r
t
e
r
s
.
5.1105
5
.
1
1
0
5
Chief
C
h
i
e
f
Counsel,
C
o
u
n
s
e
l
,
Food
F
o
o
d
and
a
n
d
Drug
D
r
u
g
Admin-
A
d
m
i
n
-
istration.
i
s
t
r
a
t
i
o
n
.
5.1110
5
.
1
1
1
0
FDA
F
D
A
Public
P
u
b
l
i
c
Information
I
n
f
o
r
m
a
t
i
o
n
Offices.
O
f
f
i
c
e
s
.
AUTHORITY:
A
U
T
H
O
R
I
T
Y
:
5
5
U.S.C.
U
.
S
.
C
.
552;
5
5
2
;
21
2
1
U.S.C.
U
.
S
.
C
.
301–397.
3
0
1
–
3
9
7
.
SOURCE:
S
O
U
R
C
E
:
77
7
7
FR
F
R
15962,
1
5
9
6
2
,
Mar.
M
a
r
.
19,
1
9
,
2012,
2
0
1
2
,
unless
u
n
l
e
s
s
otherwise
o
t
h
e
r
w
i
s
e
noted.
n
o
t
e
d
.
Subparts
S
u
b
p
a
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s
A–L
A
–
L
[Reserved]
[
R
e
s
e
r
v
e
d
]
Subpart
S
u
b
p
a
r
t
M—Organization
M
—
O
r
g
a
n
i
z
a
t
i
o
n
§
§
5.1100
5
.
1
1
0
0
Headquarters.
H
e
a
d
q
u
a
r
t
e
r
s
.
Office
O
f
f
i
c
e
of
o
f
the
t
h
e
Commissioner.
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o
m
m
i
s
s
i
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r
.
1
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Office
O
f
f
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of
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the
t
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h
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f
Counsel.
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s
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l
.
Office
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f
f
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of
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f
the
t
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x
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c
u
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i
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Secretariat.
S
e
c
r
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a
r
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a
t
.
Freedom
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d
o
m
of
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f
Information
I
n
f
o
r
m
a
t
i
o
n
Staff.
S
t
a
f
f
.
Dockets
D
o
c
k
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s
Management
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a
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m
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Staff.
S
t
a
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f
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Office
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f
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of
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the
t
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Chief
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Scientist.
S
c
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t
i
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.
1
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Office
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f
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of
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Counter-Terrorism
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of
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Regulatory
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u
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Science
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c
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and
a
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Innovation.
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n
n
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v
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i
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n
.
Division
D
i
v
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s
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n
of
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f
Science
S
c
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c
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Innovation
I
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n
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v
a
t
i
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n
and
a
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d
Critical
C
r
i
t
i
c
a
l
Path.
P
a
t
h
.
Division
D
i
v
i
s
i
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n
of
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f
Scientific
S
c
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n
t
i
f
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Computing
C
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m
p
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i
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g
and
a
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d
Med-
M
e
d
-
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i
c
a
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Information.
I
n
f
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m
a
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.
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of
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f
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of
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a
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Informatics.
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n
f
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a
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s
.
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f
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of
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s
Health.
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a
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h
.
Office
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of
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of
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Affairs.
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f
f
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Office
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f
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of
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Minority
M
i
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H
e
a
l
t
h
.
National
N
a
t
i
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n
a
l
Center
C
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n
t
e
r
for
f
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r
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T
o
x
i
c
o
l
o
g
i
c
a
l
Research.
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e
s
e
a
r
c
h
.
2
2
Office
O
f
f
i
c
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of
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f
the
t
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Center
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Director.
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f
f
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of
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a
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m
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.
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f
f
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of
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h
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D
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of
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f
Biochemical
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h
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m
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c
a
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Toxicology.
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c
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y
.
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D
i
v
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s
i
o
n
of
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f
Genetic
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e
n
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t
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c
and
a
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d
Molecular
M
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c
u
l
a
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Toxi-
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x
i
-
cology.
c
o
l
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g
y
.
1
1
Mailing
M
a
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l
i
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g
address:
a
d
d
r
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s
s
:
10903
1
0
9
0
3
New
N
e
w
Hampshire
H
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m
p
s
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Ave.,
A
v
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.
,
Silver
S
i
l
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,
MD
M
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20993.
2
0
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3
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2
2
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M
a
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l
i
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g
address:
a
d
d
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s
s
:
Food
F
o
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d
and
a
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d
Drug
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Adminis-
A
d
m
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n
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s
-
tration,
t
r
a
t
i
o
n
,
3900
3
9
0
0
NCTR
N
C
T
R
Rd.,
R
d
.
,
Jefferson,
J
e
f
f
e
r
s
o
n
,
AR
A
R
72079.
7
2
0
7
9
.
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