Innovating in the life sciences and health-care sector? You can’t escape the regulators! Before you make a costly mistake, learn from the experts who have been through the process before. Whether you’re working on a therapeutic, an in vitro diagnostic or a medical device, come find out how to identify and mitigate challenges along the path to regulatory approval.

1. Avoiding Pitfalls in the Regulatory Path
Sonia Sanhueza
September 30, 2011

2. Avoiding
Pi*alls
in
the
Regulatory
Path
Best
Prac7ce
Sessions
MaRS
Discovery
District
30
SEP
2011
Sonia
Sanhueza,
PhD
Prac7ce
Lead
&
Advisor,
Life
Science
&
Healthcare
2

3. Avoiding
Pi*alls
in
the
Regulatory
Path
1. Pharma
/
Biotech
/
Medical
Device
Product
Life
Cycle
2.
Regulatory
and
Quality
Requirements
3.
Common
Pi*alls
and
Consequences
4.
Avoiding
Pi*alls
5.
US
FDA
483
/
Warning
LeRer
6.
Summary
3

4. Product
Life
Cycle
concept
POC
Pre-­‐clin
clinical
approval
Quality
/
Regulatory
requirements
$$$$
Drugs
/
biotech
/
biologics
Claims
IFU
The
Interna'onal
Conference
on
Harmonisa'on
(ICH)
of
Technical
Requirements
for
Registra7on
of
Pharmaceu7cals
for
Human
Use
US
FDA
European
Medicine
Agency
Health
Canada
Japan’s
Pharmaceu7cal
and
Medical
Devices
Agency
(PMDA)

5. concept
prototype
Tes7ng
valida7o
n
approval
Quality
/
Regulatory
requirements
$$$$
Medical
devices
Claims
IFU
Product
Life
Cycle
5
US
FDA
Competent
Authority
in
the
MS
Health
Canada
Japan’s
Pharmaceu7cal
and
Medical
Devices
Agency
(PMDA)

6. Drugs
/
Biotech
/
Biologics
concept
POC
Pre-­‐clin
clinical
approval
$$$$
GO
/
NO-­‐
GO
R&D

7. Drugs
/
Biotech
/
Biologics
Quality
and
Regulatory
Requirements
concept
POC
Pre-­‐clin
clinical
approval
$$$$
• Legal
–
IP
/
Trademark
• Raw
materials
• CRO
–
pre-­‐clin
• Suppliers
qualifica7on
• SOPs
• Tes7ng
>
valida7on
• Reference
standards
• Processes
• Procedures
• Personnel
• Facility
• Documenta7on
GO
/
NO-­‐
GO

8.
concept
POC
Pre-­‐clin
clinical
approval
$$$$
GO
/
NO-­‐
GO
cGLP
GDP
cGMP
Drugs
/
Biotech
/
Biologics
Quality
and
Regulatory
Requirements

9.
concept
POC
Pre-­‐clin
clinical
approval
$$
$$
• Legal
–
IP
/
Trademark
• Raw
materials
• CRO
–
pre-­‐clin
• Suppliers
qualifica7on
• SOPs
• Tes7ng
>
valida7on
• Reference
standards
• Processes
• Procedures
• Personnel
• Facility
• Documenta7on
GO
/
NO-­‐GO
• Protocols
• Reports
• Document
control
• Process
valida7on
• Environmental
monitoring
• cGMP/GCP/GLP/GDP
• Sta7s7cal
analysis
• CMOs
• CROs
–
clin
• Audits
Drugs
/
Biotech
/
Biologics
Quality
and
Regulatory
Requirements

10. • General
provisions
of
current
Good
Manufacturing
• Responsibility
of
management.
• Conduc=ng
audits,
taking
correc=ve
ac=on
and
documen=ng
results.
• Crea=ng
design
controls:
input,
output,
valida=on,
transfer,
changes
and
documenta=on.
• Purchasing
and
the
evalua=on
of
suppliers.
• Iden=fica=on
and
traceability
of
products.
• Dealing
with
produc=on
and
process
changes.
• Inspec=on,
measuring
and
tes=ng
equipment.
• Acceptance
ac=vi=es.
• What
to
do
with
non-­‐conforming
products.
• Correc=ve
and
Preven=ve
Ac=ons
(CAPA).
• Labeling,
storage,
distribu=on
and
installa=on.
• Records
and
servicing
of
products.
10
Drugs
/
Biotech
/
Biologics
Quality
and
Regulatory
Requirements

11. Legal
The
US
Patent
and
Trademark
Office
(USPTO)
is
not
the
only
checkpoint
for
pharmaceu=cal
trademarks.
The
trademark
clearance
process
for
pharma
companies
consists
of
both
a
legal
and
regulatory
process
11
Drugs
/
Biotech
/
Biologics
Trademark
Regulatory
Requirement

12. In
most
cases
the
legal
process
consist
of:
• branding
concept
conceived
by
pharmaceu=cal
branding
specialists
• pool
of
poten=al
brand-­‐name
candidates
submiUed
for
considera=on
by
the
marke=ng
or
trademark
development
department
• candidates
are
typically
priori=zed
• forwarded
to
the
company’s
trademark
legal
department
or
law
firm
for
ini=al
screening
(e.g.
Trademark
db
plaXorms)
in
key
jurisdic=ons
to
weed
out
poten=ally
problema=c
candidates
• Candidates
proceed
to
a
full
trademark
legal
clearance
search
(trademark
aUorney)
• providing
a
legal
opinion
as
to
a
trademark’s
poten=al
availability
for
use
and
registra=on
in
connec=on
with
a
par=cular
product
(or
service
in
the
case
of
service
marks)
12
Drugs
/
Biotech
/
Biologics
Trademark
Regulatory
Requirement

13. Specialized
trademark
research
report
-­‐
assists
a
trademark
aUorney
in
formula=ng
a
well-­‐supported
opinion
on
availability
of
a
pharmaceu=cal
trademark.
It
should
mirror
FDA
review
process
• Should
have
a
name
safety
component
• Include
a
selec=on
of
sources
that
are
reviewed
by
the
FDA
o Orange
Book
(FDA-­‐approved
drugs)
o U.S.
Adopted
Names,
USAN,
(generic-­‐drug
names)
o include
informaEon
derived
using
known
FDA
methods,
such
as
the
FDA’s
Phone=c
and
Orthographic
Computer
Analysis
algorithm.
13
Drugs
/
Biotech
/
Biologics
Trademark
Regulatory
Requirement

14. Health
Canada
• 4.
DEFINITIONS
• Brand
name
(or
proprietary
drug
name):
C.01.001.(1)
of
the
Food
and
Drug
RegulaEons
• Chemical
name:
The
chemical
name
of
a
drug
provides
an
unambiguous
picture
of
a
molecule
so
that
a
trained
chemist
can
use
it
to
draw
its
structure
if
required
• Common
name:
C.01.001.(1)
of
the
Food
and
Drug
RegulaEons
states
that
a
"common
name"
means,
with
reference
to
a
drug,
the
name
in
English
or
French
by
which
the
drug
is
(a)
commonly
known
and
(b)
designated
in
scienEfic
or
technical
journals,
other
than
the
publicaEons
referred
to
in
Schedule
B
to
the
Act.
• Generic
name:
The
generic
or
non-­‐proprietary
name
describes
the
drug
substance.
• Health
product:
Health
products
include
pharmaceu=cals,
biologicals,
vaccines,
medical
devices,
natural
health
products,
radiopharmaceu=cals
and
veterinary
drug
products.
• Interna7onal
Nonproprietary
Name
(INN):
INNs
iden=fy
a
drug
substance
by
a
unique,
universally
applicable
and
accepted
generic
name.
It
is
noted
that
chemicals
that
do
not
have
a
defined
chemical
composi=on
or
structure
or
that
cannot
adequately
be
described
cannot
be
assigned
INNs
(i.e.,
mixtures
of
substances).
• Look-­‐alike
Sound-­‐alike
(LA/SA)
Health
Product
Names:
Health
products
that
have
a
similar
wriUen
name
or
similar
phone=cs
to
those
of
another
health
product.
• Product
line
extension:
A
product
line
extension
results
when
a
drug
is
named
by
using
the
brand
name
of
another
drug
with
the
addi=on
of
a
modifying
prefix
or
suffix
that
is
intended
to
dis=nguish
the
new
product
from
the
original
• Proper
name:
C.01.001.(1)
of
the
Food
and
Drug
RegulaEons
states
• Trade-­‐mark:
Sec=on
2
of
the
Trade-­‐marks
Act
states
that
a
trade-­‐mark
is
(a)
a
mark
that
is
used
by
a
person
for
the
purpose
of
disEnguishing
or
so
as
to
disEnguish
wares
or
services
manufactured,
sold,
leased,
hired
or
performed
by
him
from
those
manufactured,
sold
leased,
hired
or
performed
by
others,
(b)
a
cerEficaEon
mark,
c)
a
disEnguishing
guise,
or
(d)
a
proposed
trade
mark.
• Trade-­‐name:
Sec=on
2
of
the
Trade-­‐marks
Act
states
that
a
trade
name
is
the
name
under
which
any
business
is
carried
on,
whether
or
not
it
is
the
name
of
a
corporaEon,
a
partnership
or
individual.
• United
States
Adopted
Name
(USAN):
USANs
iden=fies
nonproprietary
names
for
drugs
by
establishing
simple,
logical
nomenclature
based
on
pharmacological
and/or
chemical
rela=onship.
14

15.
concept
POC
Pre-­‐clin
clinical
approval
$$$$
GO
/
NO-­‐GO
Regulatory
Agency
inspec7ons
• Clinical
sites
• Facili=es
• Pre-­‐clinical
data
Drugs
/
Biotech
/
Biologics
Trademark
Regulatory
Requirement

16. • SOPs
-­‐
dra`ed
documents,
no
signatures
of
responsible
person,
originals
not
in
place
only
photocopies,
not
enough
detail
for
operators
to
follow
procedures
• Personnel
o lack
of
appropriate
educa=on
o Lack
of
appropriate
training
o Training
not
documented
• Facili7es
o Lack
of
environmental
monitoring
program
or
unreliable
o
Cleaning
procedures
not
validated
o Airflow
velocity
inside
cri=cal
areas
not
well
defined
Drugs
/
Biotech
/
Biologics
Common
Pi*alls
16

17. Tes7ng
procedures
• Acceptance
criteria
not
established
• Specifica=ons
not
in
place
• Inappropriate
reference
standard
• Tests
not
validated
• Results
not
documented
Raw
materials
• Sourcing
material
with
undefined
impuri=es
• Supplier
not
qualified
17
Drugs
/
Biotech
/
Biologics
Common
Pi*alls

18. Clinical
• Conduct
of
clinical
trial
–
lack
of
appropriate
personnel
supervision
• Enrolment
of
subjects
that
did
not
meet
eligibility
criteria
• Failure
to
no=fy
IRB
on
protocol
changes
• Protocol
not
signed
by
inves=gator
• Failed
to
obtain
informed
consent
Customer
Complains
• Parameters
against
which
to
assess
adequacy
of
ac=ons
not
established
• SOP
not
in
place
18
Drugs
/
Biotech
/
Biologics
Common
Pi*alls

19. concept
prototype
Tes7ng
valida7o
n
approval
Quality
/
Regulatory
requirements
$$$$
Medical
devices
Claims
IFU
Product
Life
Cycle
19
US
FDA
Competent
Authority
in
the
MS
Health
Canada
Japan’s
Pharmaceu7cal
and
Medical
Devices
Agency
(PMDA)

20.
GO
/
NO-­‐
GO
R&D
MEDICAL
DEVICES
concept
prototype
Tes7ng
valida7on
approval
$$$$
• Legal
–
IP
/
Trademark
• Raw
materials
• Suppliers
qualifica7on
• SOPs
• Tes7ng
>
valida7on
• Processes
• Procedures
• Personnel
• Facility
• Documenta7on
• Design
process

21.
GO
/
NO-­‐
GO
R&D
MEDICAL
DEVICES
concept
prototype
Tes7ng
valida7on
approval
$$$$
QS
ISO
13485

22.
MEDICAL
DEVICES
Design
planning
Design
verifica7on
Design
transfer
QS
ISO
13485
inputs
outputs
Reviews
Change
control

23. concept
prototype
Tes7ng
valida7on
approval
$$$$
GO
/
NO-­‐GO
• Protocols
• Reports
• Document
control
• Process
valida7on
• Environmental
monitoring
• Sta7s7cal
analysis
• CMOs
• CROs
–
clin
• Audits
MEDICAL
DEVICES
23

24. • Gap
analysis
audit
-­‐
Audit
in
which
the
current
level
of
compliance
with
the
appropriate
quality
regula=ons
including
FDA
GMP,
ISO
13485,
Japan
PAL,
Brazilian
GMP
and/or
CMDR
is
determined
for
the
company.
The
gap
analysis
is
typically
conducted
before
a
system
is
implemented
to
iden=fy
areas
of
deficiency.
• Pre-­‐assessment
audit
–
It
is
highly
recommend
that
a
pre-­‐
assessment
audit
be
conducted
several
weeks
prior
to
a
cer=fica=on
audit.
MEDICAL
DEVICES
-­‐
Quality
Requirements
24

25. • Full
or
par7al
internal
audit
-­‐
ISO
and
FDA
QSR
(GMP)
require
that
manufacturers
conduct
regular
internal
audits
of
their
quality
management
systems.
Par=al
audits
can
be
conducted
in
which
the
auditor
focuses
on
specific
areas
of
the
quality
system
where
you
suspect
non-­‐compliance
occurs
or
have
occurred,
or
focus
on
areas
where
audits
cannot
be
conducted
by
your
in-­‐house
internal
auditor
due
to
possible
conflicts
of
interest.
• Subcontractor
or
supplier
audit
-­‐
Cri=cal
suppliers
must
be
"controlled."
This
is
not
only
a
good
business
prac=ce,
but
o`en
also
a
regulatory
requirement.
For
example,
if
your
device
is
manufactured
by
a
subcontractor,
it
is
your
responsibility
to
ensure
their
manufacturing
processes
meet
the
appropriate
standards
and
regula=ons.
25
MEDICAL
DEVICES
-­‐
Quality
Requirements

26. • ISO
13485:2003,
FDA
Good
Manufacturing
Prac=ces
(GMP),
CE
Marking
and
Canadian
Medical
Device
Regula=ons
(CMDR).
• Management
responsibili=es
to
customers,
to
quality
policy,
and
to
employees.
• Resource
management:
personnel,
materials,
infrastructure
and
facili=es.
• Product
realiza=on
from
the
planning
stages
through
design
development
through
interac=on
with
customers.
• Ways
to
measure,
evaluate,
and
improve
performance
within
the
organiza=on.
• Requirements
for
incident
repor=ng,
technical
files,
and
risk
analysis.
26
MEDICAL
DEVICES
-­‐
Quality
Requirements

27. • Procedures
for
implemen=ng
CAPA
and
document
CAPA
ac=vi=es
are
inadequate
or
non-­‐existent
• Results
are
not
documented
or
not
verified
• Procedures
not
in
place
for
the
valida=on
of
the
device
design,
design
requirements
and
document
control
• Acceptance
criteria
for
tes=ng
not
in
place
• Lack
of
maintenance
of
quality
requirements
in
regards
to
suppliers,
contractors,
consultants
MEDICAL
DEVICES
–
Common
pi*alls
27

28. • Device
history
records
(DHR)
for
each
batch,
lot,
unit
are
not
maintained
• Procedures
used
by
operators
to
manufacture
product
are
not
maintained
in
Device
master
records
(DMR)
• Lack
of
compliance
with
established
quality
system
requirements
• Companies
implement
changes
before
performing
iden=fica=on,
documenta=on,
valida=on,
verifica=on,
review,
and
approval
of
design
• Acceptance
of
specifica=ons
not
established
MEDICAL
DEVICES
–
Common
pi*alls
28

29. • Risk
process
and
analysis
not
in
place
• Design
History
File
(DHF)
–
user
needs
and
intended
uses
not
defined
• Design
valida=on
procedures
for
system
integra=on
tes=ng
for
the
device
so`ware
not
established
and
documenta=on
not
in
place
• Personnel
–
training
records
not
in
place
MEDICAL
DEVICES
–
Common
pi*alls
29

30. • Regulated
companies
-­‐
opportunity
to
engage
with
healthcare
consumers
and
healthcare
professionals
who
are
increasingly
using
the
internet
to
find
health
informa=on
• To
avoid
regulatory
piXalls
it
is
important
to
have
expert
counsel
to:
o address
product
risk
informa=on
o consumer-­‐generated
discussion
of
off-­‐label
uses
o online
communica=ons
o interac=on
between
consumers
and
healthcare
providers
about
health
topics
that
have
an
impact
on
pa=ent
health
• The
team
tasked
with
overseeing
the
design
and
execu=on
of
a
social
media
campaign
should
be
mul=disciplinary:
marke=ng,
corporate,
regulatory,
medical
affairs,
legal
&
other
relevant
internal
par=es
ROL
OF
SOCIAL
MEDIA
in
REGULATED
COMPANIES
30

31. Guidelines
US
FDA
–
no
official
guideline,
release
informa=on
expected
soon
EU
–
only
internet
communica=on
in
general
It
is
important
to
know
the
boundaries
of
what
will
and
will
not
be
permiUed
31
ROL
OF
SOCIAL
MEDIA
in
REGULATED
COMPANIES

32. TIME
IS
MONEY
=
REVENUES
LACK
OF
CREDIBILITY
=
INVESTORS
LOST
MARKET
=
COMPETITIVE
POSITION
Common
pi*alls
–
Consequences
/
Impact
32

33. US
FDA
will:
• Request
prompt
ac=on
with
consequences
for
lack
of
ac=on:
o Seizure
o Injunc=ons
o Civil
money
penal=es
• Address
leUer
within
15
business
days
• Withhold
approval
of
any
new
applica=on
or
supplements
lis=ng
the
firm
as
a
drug
manufacturer
• Refusal
by
FDA
of
product
manufactured
at
foreign
facility
to
entry
into
the
USA
• Be
aware:
Not
intended
to
be
an
all-­‐inclusive
list
of
viola=ons
Common
pi*alls
-­‐
Consequences
33

34. US
FDA
WARNING
LETTERS
Drugs
/
Biotech
/
Biologics
34

35.
US
FDA
Form
483
and
/
or
Warning
LeRer
• FDA
Form
483
is
referred
to
as
"No=ce
of
Inspec=onal
Observa=ons."
• The
483
is
issued
by
the
FDA
field
inves=gator
a`er
an
on-­‐site
inspec=on
• It
lists
deficiencies
in
your
quality
system.
• The
observa=ons
are
based
on
the
inspector's
interpreta=on
of
the
regula=ons
as
they
relate
to
your
opera=onal
GMP
quality
system.
• The
field
inspector
will
submit
the
finalized
483
to
his/her
superiors;
based
on
the
severity
of
the
findings,
an
FDA
Warning
LeUer
may
be
issued
to
your
firm.
35

36. • You
must
respond
to
the
483
promptly
within
a
=meframe
specified
by
the
FDA.
• Analyze
the
findings
of
the
FDA
Form
483
and/or
Warning
LeUer
• Chart
a
course
of
ac=on
for
your
company
• Propose
"Correc=ve
Ac=ons“
(CA)
to
be
made
to
your
quality
system.
• Provide
a
detailed
response
for
each
item
addressed
in
the
483.
The
quality
and
promptness
of
your
response
to
this
leUer
are
extremely
important
• Suggest
an
appropriate
=meline
to
sa=sfy
the
FDA
• Assist
in
implemen=ng
correc=ve
ac=ons
in
response
to
FDA
Form
483.
• Be
available
to
answer
all
ques=ons
from
you
or
the
FDA
during
your
efforts
to
correct
the
noted
deficiencies
US
FDA
Form
483
and
/
or
Warning
LeRer
(cont’d)
36

37. GCP
compliance
Clinical
inves=gato
r

38. Document
control
safety
and
validity
of
data
38

39. compliance
CAPA
15
bus.
days
39

40. procedures
Drug
cGMP
40

41. personnel
Dras=c
consequences
41

42. QS
Medical
devices
42

43. Doc.
Procedures
Controls
QS
DHR
43

44. QSR:
DMR
procedures
44

45. 45

46. -­‐Specs
-­‐Risk
-­‐Valid’n
-­‐Intended
use
-­‐DHF
-­‐
Process
46

47. Process
CAPA
Complains
47

48. 48

49. Hospital
Post-­‐
approval
inspec=on
documenta=on
49

50. Dras=c
consequences
50

51. Summary
• Start
with
the
end
in
mind
-­‐
what
is
your
claim?
• Don’t
cut
corners
• Get
exper=se
to
help
you
prepare
the
Regulatory
Requirements
&
Quality
System
– audit
your
quality
system
on
a
regular
basis
to
ensure
compliance
with
the
appropriate
regula=ons
and
standards
in
compliance
with
the
FDA
Quality
System
Regula=on,
European
Device
Direc=ves,
Japan's
PAL,
Brazilian
GMP
and
Canadian
Medical
Device
Regula=ons
(CMDR).
– Failure
to
do
so
can
result
in
poor
product
quality,
loss
of
cer=fica=on
or
lack
of
process
improvement.
• Key
elements
to
have
in
place:
processes,
procedures,
documenta=on,
controls,
training
• Plan
for
tomorrow
51

52. THANK
YOU
FOR
YOUR
ATTENTION
Q&A
52