FDA CIRCULAR
 
No. ___________
 
 
 
TO               :
ALL MANUFACTURERS/ TRADERS/ IMPORTERS OF
 
 
HEATED TOBACCO PRODUCTS.
 
 
 
SUBJECT
:
​
PROCEDURE
FOR
PRE-APPLICATION
DOCUMENTARY
 
 
 
 
 
 
 
EVALUATION
(PADE)
FOR
HEATED
TOBACCO
 
 
 
 
 
PRODUCTS
SEEKING
ELECTRONIC
REGISTRATION
 
 
 
 
NUMBERS
(FERNs)
UNDER
THE
FOOD
AND
DRUG
 
 
 
 
 
 
 
ADMINISTRATION
 
I.
BACKGROUND
 
 
 
Pursuant
to
Republic
Act
No.
11467,
Republic
Act
9711,
and
Executive
 
 
 
 
 
 
 
 
 
 
 
Order
No.
106,
the
Food
and
Drug
Administration
(FDA)
is
mandated
to
regulate
Heated
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco
Products
(HTPs)
consistent
with
evolving
medical,
public
health,
and
scientific
 
 
 
 
 
 
 
 
 
 
 
evidence.
To
this
end,
the
FDA
hereby
implements
this
Circular
applicable
to
all
HTP
 
 
 
 
 
 
 
 
 
 
 
 
 
 
refills, cartridges and electronic delivery devices.
 
 
 
II.
OBJECTIVE
 
This
Circular
is
being
issued
to
provide
the
supplemental
procedures
and
 
 
 
 
 
 
 
 
 
 
 
guidelines
for
the
issuance
of
a
Pre-application
Documentary
Evaluation
(PADE)
 
 
 
 
 
 
 
 
 
 
certificate
as
part
of
the
requirements
of
HTP
registration
for
the
issuance
of
an
FDA
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electronic Registration Number (FERN) certificate.
 
 
 
 
III.
SCOPE AND COVERAGE
 
This
Circular
shall
cover
all
manufacturers,
traders,
and
importers
that
 
 
 
 
 
 
 
 
 
 
seek to apply for a FERN certification of their HTPs.
 
 
IV.
GENERAL PROCEDURE
 
 
1.
Manufacturers,
traders,
and
importers
of
HTPs
who
intend
to
apply
for
FERN,
shall
 
 
 
 
 
 
 
 
 
 
 
 
 
submit
an
application
for
PADE
at
least
one
hundred
twenty
(120)
calendar
days
as
 
 
 
 
 
 
 
 
 
 
 
 
 
 part
of
the
documentary
requirements
for
HTP
FERN
certification
under
the
Center
for
 
 
 
 
 
 
 
 
 
 
 
 
 
Cosmetics Regulation and Research (CCRR).
 
 
2.
Submission
of
PADE
shall
be
done
electronically,
through
FDA’s
current
e-portal
 
 
 
 
 
 
 
 
 
 
 
system for HTPs.
 
 
3.
The
FDA
shall
automatically
disapprove
applications
with
incomplete
or
incorrect
 
 
 
 
 
 
 
 
 
 
submissions.
 
 
4.
The
CCRR
may
request
for
additional
information
and
documents
from
the
applicant
 
 
 
 
 
 
 
 
 
 
 
 
should there be any clarification on the submitted documents.
 
 
5.
The
final
disposition
on
the
evaluations
shall
lie
solely
with
the
Director
General
of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the FDA upon the recommendation of the Director IV of the CCRR.
 
 
6.
Under
no
circumstances
shall
evaluations
with
favorable
dispositions
be
deemed
as
an
 
 
 
 
 
 
 
 
 
 
 
 
imprimatur
of
FDA
approval
nor
shall
nor
shall
it
mean
the
approval
of
a
product
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
claim.
Any
industry
promotion,
advertisement,
or
communication,
explicit
or
implicit,
 
 
 
 
 
 
 
 
 
 
contrary
to
this
provision
shall
be
grounds
for
immediate
and
final
denial
of
active
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HTP applications on the said product.
 
 
V.
SPECIFIC GUIDELINES
 
1.
The Pre-Application Documentary Evaluation shall contain the following documents:
 
 
1.1.
Administrative Data if MAH
 
1.1.1.
Complete company information, including:
 
1.1.1.1.
Company name
 
1.1.1.2.
Organizational chart
 
1.1.1.3.
Business addresses and other contact details
 
1.1.1.4.
Notarized
authorized
responsible
person
to
apply
in
behalf
of
the
 
 
 
 
 
 
 
 
 
 
manufacturer, in case the applicant is a distributor or importer.
 
1.1.2.
Authorization
for
the
FDA
to
use,
copy,
store,
and
distribute
digital
and
 
 
 
 
 
 
 
 
 
 
 
 
physical
copies
of
all
documents
submitted
to
FDA
for
the
purposes
of
 
 
 
 
 
 
 
 
 
 
 
 
(1)
review
and
evaluation
of
the
application;
(2)
enforcement;
and
(3)
 
 
 
 
 
 
 
 
 
 
 
conduct
of
research
for
the
development
of
regulatory
standards
and
 
 
 
 
 
 
 
 
 
 
public
health
policies.
All
information
and
documents
submitted
to
the
 
 
 
 
 
 
 
 
 
 
 
FDA
shall
be
deemed
as
Confidential
Information
and
shall
be
 
 
 
 
 
 
 
 
 
 
protected
in
accordance
with
the
Data
Privacy
Act
​
with
respect
to
 
 
 
 
 
 
 
 
 
 
 
personal
data,
the
Department
of
Health’s
Freedom
of
Information
 
 
 
 
 
 
 
 
 
Manual,
and
also
in
accordance
with
other
applicable
laws,
rules
and
 
 
 
 
 
 
 
 
 
 
 regulations,
and
existing
jurisprudence
protecting
Confidential
 
 
 
 
 
 
information
​
.
 
 
Confidential
Information
for
purposes
of
this
Circular
shall
include
 
 
 
 
 
 
 
 
 
personal
data,
trade
secrets,
intellectual
property,
business,
commercial,
 
 
 
 
 
 
 
 
financial,
or
proprietary
information,
or
any
other
information
or
date
 
 
 
 
 
 
 
 
 
 
that by its nature should be kept confidential.
 
 
1.1.3.
An
attestation
from
the
manufacturer,
trader,
or
importer
that
the
 
 
 
 
 
 
 
 
 
 
information
contained
in
the
bundle
is
complete,
accurate,
and
 
 
 
 
 
 
 
 
 
unredacted, under the penalties of all relevant legislation.
 
1.2.
Data on Raw Materials
 
1.2.1.
Administrative Data and Information
 
1.2.1.1.
Name and address of the manufacturer
 
1.2.1.2.
Name and address of the supplier
 
 
1.2.2.
Chemistry, Manufacturing and Controls
 
1.2.2.1.
General properties
 
1.2.2.2.
Schematic
flow
diagram
and
sequential
procedural
narrative
of
the
 
 
 
 
 
 
 
 
 
manufacturing process
 
1.2.2.3.
Materials used in the manufacture of the components
 
1.2.2.4.
Technical specifications
 
1.2.2.5.
Analytical Procedures
 
 
1.3.
Data on Finished Product
 
1.3.1.
Administrative Data and Information
 
1.3.1.1.
Name and address of the manufacturer
 
1.3.1.1.1.
LTO number (for local manufacturers)
 
1.3.1.2.
Name and address of the supplier (for imported products)
 
 
1.3.2.
Chemistry, Manufacturing and Control
 
1.3.2.1.
Qualitative and quantitative composition of the product
 
1.3.2.2.
Compatibility of the ingredients/components
 
1.3.2.3.
Master Formula per batch size
 
1.3.2.4.
Schematic
flow
diagram
and
sequential
procedural
narrative
of
the
 
 
 
 
 
 
 
 
 
manufacturing process
 
1.3.2.5.
Complete list of equipment used during the manufacturing process
 
1.3.2.6.
Process validation
 
1.3.2.7.
Technical specifications
 
1.3.2.8.
Analytical procedures
 
1.3.2.9.
Validation of analytical procedures
 
1.3.2.10.
Batch analyses
 
1.3.2.11.
Characterization of impurities
 
1.3.2.12.
Container closure system
 1.3.2.13.
Stability
 
 
1.4.
Toxicological Risk Assessment
 
 
1.4.1.
Certificates
of
Analysis
for
the
panel
of
Harmful
and
Potentially
 
 
 
 
 
 
 
 
 
 
Harmful
Chemicals
(HPHC)
in
Tobacco
Products
as
listed
in
the
United
 
 
 
 
 
 
 
 
 
 
 
States
Food
and
Drug
Administration
panel,
as
tested
under
conditions
 
 
 
 
 
 
 
 
 
 
outlined
by
the
World
Health
Organization
(WHO)
Tobacco
Laboratory
 
 
 
 
 
 
 
 
 
Network
(TobLabNet)
or
Health
Canada,
relative
to
typical
emissions
 
 
 
 
 
 
 
 
 
of
the
University
of
Kentucky
reference
cigarette
3R4F,
and
as
obtained
 
 
 
 
 
 
 
 
 
 
 
under
the
Health
Canada
intense
smoking
protocol
(55mL
puff
volume
 
 
 
 
 
 
 
 
 
 
every
30
seconds,
with
100%
of
ventilation
mechanisms
occluded,
until
 
 
 
 
 
 
 
 
 
 
exhaustion
or
complete
consumption
of
the
Heated
Tobacco
Product
 
 
 
 
 
 
 
 
 
cartridge),
for
mainstream
and
sidestream
emissions,
as
determined
by
 
 
 
 
 
 
 
 
 
an
ISO-certified
government
or
independent
laboratory
that
is
not
 
 
 
 
 
 
 
 
 
owned,
partly
owned,
or
otherwise
controlled
by
the
tobacco
industry
 
 
 
 
 
 
 
 
 
 
and their agents and/or representatives.
 
1.4.2.
Results
of
the
following
in
vitro
tests
on
product
emissions,
as
 
 
 
 
 
 
 
 
 
 
 
determined
by
ISO-certified
government
or
independent
laboratories
 
 
 
 
 
 
 
not
owned,
partly
owned,
or
otherwise
controlled
by
the
tobacco
 
 
 
 
 
 
 
 
 
 
industry and their agents and/or representatives:
 
1.4.2.1.
Salmonella/microsome
fluctuation
(Ames)
Test
following
the
 
 
 
 
 
 
OECD 471 protocol
 
1.4.2.2.
In vitro dosimetric and cytotoxic assessment by neutral red uptake
 
1.4.2.3.
Mouse
Lymphoma
Assay,
in
accordance
with
the
OECD
490
 
 
 
 
 
 
 
 
 
protocol
 
1.4.3.
Results
of
the
following
in
vivo
tests
on
product
emissions,
as
 
 
 
 
 
 
 
 
 
 
 
determined
by
ISO-certified
government
or
independent
laboratories
 
 
 
 
 
 
 
not
owned,
partly
owned,
or
otherwise
controlled
by
the
tobacco
 
 
 
 
 
 
 
 
 
 
industry and their agents and/or representatives:
 
1.4.3.1.
90-day Nose-only Inhalation Studies
 
1.4.3.2.
18-month Carcinogenicity Study with A/J mice
 
1.4.3.3.
Nicotine Pharmacokinetic (PK) Study with Rats
 
1.4.4.
Results
of
the
following
systems
toxicology
studies
on
product
 
 
 
 
 
 
 
 
 
emissions,
as
determined
by
ISO-certified
government
or
independent
 
 
 
 
 
 
 
 
laboratories
not
owned,
partly
owned,
or
otherwise
controlled
by
the
 
 
 
 
 
 
 
 
 
 
tobacco industry and their agents and/or representatives:
 
1.4.4.1.
Acute
and
Repeated
Exposure
Studies
with
Human
Bronchial
 
 
 
 
 
 
 
 
Epithelial Cells
 1.4.4.2.
ApoE-/- Mouse Switching Study
 
1.5.
Clinical Behavioral Pharmacology
 
1.5.1.1.
Pharmacokinetic/Pharmacodynamic (PK/PD) Studies
 
1.5.1.2.
Intrinsic
and
Extrinsic
Factors
Affecting
Nicotine
 
 
 
 
 
 
Pharmacokinetic Data
 
1.5.1.3.
Nicotine Equivalents (NEQ) in Urine
 
1.5.1.4.
Use Behavior and Topography
 
1.5.1.5.
Product Use/Consumption
 
1.5.1.6.
Product Acceptability
 
1.5.1.7.
Product Abuse Potential
 
1.6.
Laboratory Competency
 
1.6.1.
A
complete
list
of
relevant
certifications
held
by
the
laboratory
 
 
 
 
 
 
 
 
 
 
conducting the in vitro, in vivo, and systems toxicology studies.
 
1.6.2.
An
attestation
from
the
said
laboratory
of
the
exact
make,
model,
and
 
 
 
 
 
 
 
 
 
 
 
 
brand of the smoking robot used in the conduct of the in vitro studies.
 
1.6.3.
A
complete
declaration
of
interest
of
all
researchers
conducting
the
 
 
 
 
 
 
 
 
 
 
clinical
and
behavioral
pharmacology
evaluation
and
their
relevant
 
 
 
 
 
 
 
 
qualifications and affiliations.
 
 
VI.
APPROVAL
 
Approval
of
the
PADE
shall
mean
that
the
Marketing
Authorization
Holder
may
 
 
 
 
 
 
 
 
 
 
 
 
already apply for FERN under for the specific HTP product combination.
 
 
VII.
FEES
 
 
Per submission shall have a fee of Php 50,000.00 plus a legal research fee of 1%.
 
 
VIII.
PENALTIES
 
Violation
to
any
provisions
of
this
Circular
shall
be
subject
to
the
 
 
 
 
 
 
 
 
 
 
 
 
penalties/sanctions
provided
under
Book
III,
Article
XI
of
the
Rules
and
Regulations
 
 
 
 
 
 
 
 
 
 
 
 
Implementing
Republic
Act
No.
9711,
Republic
Act
No.
11467,
Executive
Order
No.
 
 
 
 
 
 
 
 
 
 
 
 
106 and other penalties provided by other applicable laws.
 
IX.
SEPARABILITY CLAUSE
 
If
any
provision
in
this
Circular,
or
application
of
such
provision
to
any
 
 
 
 
 
 
 
 
 
 
 
 
 
circumstances,
is
held
invalid,
the
remainder
of
the
provisions
in
this
Circular
shall
not
be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
affected.
 X.
EFFECTIVITY
 
This
Circular
shall
take
effect
15
days
after
publication
in
a
newspaper
of
general
 
 
 
 
 
 
 
 
 
 
 
 
 
 
circulation and the Office of National Administrative Register of the UP Law Center.