INTERN FINALS

EXERCISE 8
http://apps.who.int/phint/en/p/docf/
http://www.pharmamanufacturing.com/articles/2009/079/

EXERCISE 9A
AO No 56 s. 1989
January 3, 1989
Subject: Revised Regulations For The Licensing
Of Drug Establishments And Outlets
RA 6675: Establishments in the pharmaceutical
industry:
I.
Drug
Establishment
means
any
organization or company involved in the
manufacture,
importation,
repacking
and/or distribution of drugs or medicines.
II.
Drug Outlet means drugstore, pharmacy,
and other business establishment which
sells drugs or medicines.
CHAPTER I - DRUG ESTABLISHMENTS
Types of Drug Establishments
1. Drug
Manufacturer
means
any
establishment engaged in operations
involved in the production of a drug,
including
propagation,
processing,
compounding, finishing, filling, packing,
repacking, altering, ornamenting and
labelling with the end in view of storage,
distribution or sale of the product:
provided that for the purpose of this
regulation the compounding and filling of
prescriptions in drugstores and hospital
pharmacies shall not be considered as
production operations.
2. Drug Trader means any establishment
which is a registered owner of the drug
product, procures the materials and
packaging components, and provides the
production monographs, quality control
standards and procedures, but subcontracts, the manufacture of such product
to a licensed manufacturer. In addition, a
trader may also engage in distribution,
and/or marketing of its products.
3. Drug Distributor/Importer means any
establishment that imports raw materials,
active ingredients and/or finished products
for its own use or for wholesale distribution
to other drug establishments or outlets.

4. Drug Distributor/Exporter means any

drug establishment that exports raw
materials, active ingredients and/or
finished products to another country.
5. Drug Distributor/Wholesaler means
any drug establishment that exports raw
materials, active ingredients and/or
finished
products
from
local
establishments for local distribution on
wholesale basis.
Standards and Requirements for License to
Operate (LTO)
General Requirements
Application
standard petition form (name, age,
citizenship and a passport size picture
(5x5) of the petitioner and other pertinent
circumstances)
Proof of registration as an establishment
single
proprietorship

certificate of
Business Name
Registration

partnership,
corporations
and other
juridical
persons

Certificate of
Registration

Bureau of
Domestic Trade
(BDT)
Securities and
Exchange
Commission
(SEC) and the
Articles of
Incorporation
of Partnership

Certificate
of
Registration
of
the
Establishments
Filipino
Pharmacist
issued by the Professional Regulation
Commission (PRC).
Certificate of attendance to a BFAD
sponsored
/accredited
seminar
on
Licensing of Drug Establishments.
affidavit of Undertaking
o Change the establishment's name if
o Display approved LTO in a
conspicuous place
o Notify BFAD
List of products to be manufactured or
distributed identified by their generic
names and brand names if any.
contract of Lease
certificate of continuing compliance
Batch Distribution Record Book
registered with BFAD.
contingency plan for recall
secure system of filling up to date
invoices pursuant to BFAD Memo Circular
No. 001 s. 1983.
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Specific Requirements
Drug Manufacturer

Guidelines on Current Good Manufacturing

Practices (A.O. No. 220 s. 1974)
Minimum standards for pharmaceutical
manufacturing equipment/machines (Annex
A)
Minimum standards for quality control
facilities (Annex B)
Certificate registered in the country of origin,
authenticated by the territorial Philippine
Consulate.
If
inspection
of
foreign
manufacturer by BFAD is necessary, cost of
inspection shall be borne by applicant
establishment.

Drug Trader

Valid contract agreement with a BFADLicensed

manufacturer
containing
a
stipulation that both the drug trader and the
manufacturer are jointly responsible for the
quality of the product.
Registered with the country of origin, duly
authenticated by the territorial Philippine
Consulate.
If
inspection
of
foreign
manufacturer by BFAD is necessary, cost of
inspection shall be borne by applicant
establishment.
description of the production process and
quality control procedures to be followed by the
contracted manufacturer, jointly certified by
the owner and the pharmacist

Foreign Agency Agreement between the

Philippine importer and foreign supplier duly
authenticated by the territorial Philippine
Consulate.
Registered in the country of origin,
authenticated by the territorial Philippine
Consulate.
If
inspection
of
foreign
manufacturer is necessary, cost of inspection
shall be borne by the applicant establishment.
(finished products) Certificate of Free Sale
in the country of origin, authenticated by
territorial Philippine Consulate.
Valid
contract
manufacturer

with

BFAD

licensed

Wholesalers

Administrative Sanctions
Grounds for Revocation of LTO

Exporters

Grounds for non-renewal of LTO:

Failure to comply
Serious, repeated or rampant violation
Persistent

Drug Distributors
Importers

Other Additional Requirements

Renewal of License to Operate (LTO)
Validities
for
all
categories
of
drug
establishments:
1) Initial Period (Initial Application) 1 year
2) Subsequent
Period
(Renewal
Application) 2 years
*At least one month prior to the expiration of
LTO, drug establishments shall renew license.

valid
contract
with
BFAD
licensed
manufacturer, trader or distributor
certificate that products are registered with
BFAD

Misrepresentation of any material fact

(Manufacturer and traders) Deficiency in GMP
that is likely to result in adulterated,
misbranded, substandard or unsafe products
as determined by BFAD. This includes among
others, grossly inadequate premises, lack of
key technical and professional personnel, lack
of key equipment in production or quality
control, poor or inadequate process control and
inadequate or improper documentation of the
production process.
(Distributors) distribution of fake, misbranded,
adulterated or unsafe drug products.
Violation of BFAD standards of quality,
efficacy, purity and safety of drug products.
Sale or distribution of antibiotic products
without batch certification by BFAD.
Failure to take adequate remedial or corrective
measures for deficiencies
Failure to keep up to date, secure, orderly, and
easily inspected records that would indicate
continued compliance

Grounds for Suspension of LTO

Minor deficiencies in GMP likely to result in

adulterated, misbranded, substandard or
unsafe products as determined by BFAD. This
includes, among others, poor housekeeping,
inadequate storage facilities, lack of minor
equipment or requirement and other minor
shortcomings.
Lapses in record keeping of invoices, receipts or
distribution records.

Re-application after Revocation

No establishment whose LTO was revoked
may apply for an LTO within 5 years
after the revocation of its license.

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Schedule of Fees
*Upon application for LTO, the following nonrefundable fees shall be charged for each
application:

*If belonging to more than one categories, apply

for LTO for each of the category and pay a
corresponding fee.
*Only upon payment of application fee may the
application be processed.
*surcharge of 50% of the above fees shall be
imposed on applications for renewal filed after the
validity of the license has lapsed.
*Any change in the category of drug
establishment or change in ownership shall
require a new application.
EXERCISE 9B
AO No. 67 s. 1989
March 15, 1989
Subject: Revised Rules and Regulations on
Registration of Pharmaceutical Products
This A.O. gives a comprehensive guidelines on the registration
of pharmaceutical products and to be consistent with R.A.
6675 known as the Generic Act of 1988.

DEFINITION OF TERMS

Registration

Pharmaceutical
Product

Drug for
General Use
Drug for
Restricted use

process of approval for the

manufacture, importation,
exportation, sale, offer for sale,
distribution or transfer of
pharmaceutical products
containing active ingredients of
known chemical structure and
properties determined to be safe,
efficacious and of good quality
according to standards of BFAD.
zPharmaceutical or biological
product containing active
ingredients responsible for its
desired effect intended for use in
the diagnosis, cure, mitigation,
treatment or prevention of
disease or to affect the structure
or function of the body of man or
animal
drug approved for sale to the
general public without restriction
other than the usual
drug approved for sale to the
general public under certain
conditions

GENERAL STANDARDS
Fully disclose all pertinent documentation
and information regarding the product.
Failure to fully disclose is ground for
disapproval and basis for withdrawal of
the establishment's license to operate.
Action on registration application shall be
based on the complete set of specifications
of the drug product proposed to appear in
the label (formulation, dosage form,
strength, therapeutic indication and
manufacturer)
Any change in any of the above
specifications will require a new
registration.
ANNOTATIONS: BFAD Circular #12 s. 1991 was issued to
clarify the requirements for a new registration when there is a
change of manufacturer without any change in other
specifications covered by Section 2.2 or A.O. 67 s. 1989. A
conditional certificate of product registration may be
granted to establishments which changes manufacturers for
its product to one that has better technical capabilities.

Action on registration application shall

include classification of the drug product
Any change in classification shall require a
new registration.
Revised standard and evaluation methods
shall be made applicable
Only establishments with a valid license to
operate can apply to register a drug
product.

CLASSIFICATION
*Number of Active Ingredients
Single Ingredient
Fixed-dose combination of two or more
ingredients
*Available
scientific
evidence
and
experience on the drug's use
"Investigational Drug" new chemical
or structural modification of a Tried and
Tested or Established Drug. Needs further
clinical pharmacology studies (Phase I, II
or III) to determine its safety and efficacy,
and meets the requirements of a new drug.
"New Drug" new chemical or structural
modification of a Tried and Tested or
Established Drug, which has undergone
adequate clinical pharmacology Phase I, II
and III. Needs further Phase IV before it
can be given regular registration.
"Tried and Tested Drug" drug which
has been used for at least (5) years and
involving at least 5,000 patients.
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 "Established Drug" safety and efficacy

has been demonstrated through long years
of general use and can be found in current
official USP-NF, and other internationallyrecognized pharmacopoeia.
"Pharmaceutical
or
therapeutic
innovation of a Tried and Tested or
Established Drugs"
o new indication(s)
o new mode of administration
o new dosage form
o new fixed dose combination of two
or more active ingredients
*Pharmacologic/therapeutic
specified in the PNDF

category

as

*Source
or
circumstances
of
drug
production
Imported as finished
Locally manufactured from imported
materials
Locally manufactured from local materials
*Brand identification and patent protection
of the drug
Branded and patented
Branded and off patent
Unbranded and off-patent (generic drug)
*Prescribing and dispensing regulations
applicable
OTC Drug or Non-Prescription
Ethical or Prescription Drug
Dangerous Drugs (List-A Drugs)
ANNOTATION: MOA between BFAD and DDB to process
registration of dangerous drugs. The Agreement makes DDB
responsible to evaluate certain registration data before
BFAD will decide on the application for registration of a
dangerous drug.

Drugs requiring strict precaution in

prescribing and dispensing (List-B Drugs)
INITIAL PRODUCT REGISTRATION
Application
- file an application under oath (Annex I)
Evaluation by review of submitted data
- BFAD evaluates the submitted data
- determines if the data is complete
- determines if drug product meets BFAD
standards
for
safety,
efficacy
or
therapeutic value (Annex II)

Evaluation by Testing of Submitted Samples

- BFAD evaluates submitted samples of
drug product
- evaluation shall cover tests for quality,
purity
and
other
physico-chemical
qualities
Assessment of Findings
- At any point during the evaluation, BFAD
may conclude that the product does not
meet the standards application shall be
denied
- At the end of the evaluation, BFAD shall
arrive at a recommendation: action on
registration application
Action on Registration Application
1) Disapproval of application for failure to
meet standards
2) Disapproval of application for lack of
qualifications
required
from
drug
establishment.
3) Approval for investigational use
4) Approval for monitored release three
years under limited sale with monitoring
procedures and subject to annual
evaluation
5) Approval for general use five years
renewable every five years
6) Approval for restricted use five years
renewable for five years
Grounds for Disapproval
product does not meet current, BFAD
standards of identity, purity, strength,
quality, safety, efficacy and therapeutic
value
label of the drug product is false and
misleading or does not conform with
current labelling requirements
Applicant materially misrepresented or
withheld significant data or information
regarding the product
Applicant failed to comply with the
requirements for registration.

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Grounds for Limited Approval

Investigational Drug
Application

New Drug Application

- results of prior animal

studies
are
found
adequate to warrant
further
clinical
pharmacology
studies
(Phase I, II and/or III)
- protocol submitted are
found to be adequate and
scientifically sound in
experimental design
- clinical
investigator
determined by BFAD to
be competent and reliable

- results of prior animal

studies
are
found
adequate and clinical
pharmacology Phase I, II
and III show that New
Drug
is
safe
and
efficacious when used for
its therapeutic indication
- protocol for monitored
release study is adequate
and scientifically sound
in experimental design
- clinicians and medical
centers to be involved are
determined by BFAD to
be competent and reliable

Ground for Approval

application supported by substantial
evidence showing drug to be safe,
efficacious and good quality
methods used in, as well as the facilities
and controls used for, manufacture of the
drug are adequate to assure its identity,
strength, quality and purity
label of the drug is a correct representation
of such drug and conforms with current
labelling requirements

APPEAL: Secretary of Health

SEPARABILITY CLAUSE
In case any provision of this administrative order is declared
contrary to law or unconstitutional, other provisions which
are not affected thereby shall continue to be in force and in
effect.

EFFECTIVITY: 15 days after its publication in a

newspapers of general circulation.
Secretary: (Sgd) ALFREDO R.A. BENGZON

RENEWAL OF REGISTRATION
-

Only drug products registered for general and

restricted use
Application for renewal of registration shall be
made on a form promulgated by BFAD.
Renewal application shall be reviewed and
evaluated on the basis of the product and the
applicant meeting the current BFAD standards
of identity, purity, strength, quality, safety,
efficacy and therapeutic value.

SCHEDULE OF REGISTRATION
Upon application for registration of a drug
product, the following non-refundable annual
fees to be paid in full for the entire period of
registration shall be charged.

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AO 2011-0009
JUL 12, 2011
Subject: National Policy and Program on Pharmacovigilance
Adverse Drug Event (ADE) or Adverse Drug Experience
Any untoward medical occurrence during treatment with a
pharmaceutical product but which does not necessarily
have a causal relationship with such treatment
Adverse Event (AE)
Any untoward medical occurrence during usage of a drug,
but which does not necessarily have a causal relationship
with the product
Adverse Drug Reaction (ADR)
Response to a drug which is noxious, unintended, and
which occurs at doses normally used in man for the
prophylaxis, diagnosis, or therapy of disease, or for the
modification of physiological function
Contract Research Organization (CRO
Person or organization contracted by the sponsor to
perform one or more of a sponsor's trial-related duties and
functions
Expedited Reporting
Submission of reports of serious and unexpected adverse
reaction within (7) working days from the occurrence of
such serious adverse reaction
Healthcare Professional
any doctor of medicine, doctor of veterinary medicine,
doctor of dental medicine, pharmacist, nurse, midwife, or
any other healthcare professional or practitioner duly
licensed to practice in the Philippines
Market Authorization Holder (MAH)
Any legal entity responsible for introducing a product in
Philippine market, and which has been granted
authorization by the FDA upon issuance of a Certificate of
Product Registration (cPR)
National Pharmacovigilance center (NPVC)
Primary Pharmacovigilance unit that coordinates the
Regional Pharmacovigilance units and the implementing
authority of the National Pharmacovigilance Program
National Pharmacovigilance Program (NPVP)
Nationwide program which oversees the collection,
collation, review and analysis of adverse events and other
problems concerning drug products from professionals,
consumers, the industry and other regulatory bodies for
use in setting and updating policy direction and regulatory
action and thus, ensure public safety from the use of drugs
and medicines through timely dissemination of current and
updated information.
Periodic Safety Update Report (PSIIR)
Report submitted by a pharmaceutical company intended
to provide an update on the worldwide safety experience of
a drug after it has been approved and registered with FDA
Peripheral Pharmacovigilance Units (PhPVu)
Pharmacovigilance units from relatively smaller medical
institutions including individual medical practitioners'
clinics, private hospitals, nursing homes, pharmacies etc.
They will also function as first contact AE data collection
units.
Pharmaceutical Product
Any preparation for human use that is intended to modify
or explore physiological systems or pathological states for
the benefit of the recipient
Pharmacovigilance Units (PVu)
Refers to the National Center, Regional and Peripheral
Pharmacovigilance
units
of
the
National
Pharmacovigilance Program
Post Registration Study or Post-Marketing Study
Any study conducted within the conditions of registration
or under normal conditions of use and within the
knowledge of the MAH

Product Defect Report

Reports pertinent to, but not limited to the following, lack
of efficacy, product defect, counterfeiting or false claims in
advertisements
Regional Pharmacovigilance Units (RPVu)
Secondary Pharmacovigilance units of relatively larger
healthcare facilities attached with medical colleges. They
shall act as second level centers in the administrative
structure of the National Pharmacovigilance Program
Function as first contact ADE data collection units
Registry
Organized system for the collection, storage, retrieval,
analysis, and dissemination of information on individual
persons exposed to a specific medical intervention who
have either a particular disease (risk factor) that
predisposes them to the occurrence of a health-related
event, or have prior exposure to substances known or
suspected to cause adverse health effects
Serious Adverse Event or Reaction
Any untoward medical occurrence that at any dose results
in death, requires inpatient hospitalization or prolongation
of existing hospitalization, results in persistent or
significant disability/incapacity and is life-threatening
Signal
Reported information on a possible causal relationship
between an adverse event and a drug, the relationship
being unknown or incompletely documented previously
Spontaneous report
Unsolicited communication by healthcare professionals or
consumers to a company, regulatory authority or other
organization that describes one or more adverse reactions
in a patient who was given one or more drugs
Not derived from a study or any organized data collection
scheme
Spontaneous reporting
Regional or country-wide system for the reporting of
suspected adverse events which is the major source of
information in Pharmacovigilance
Therapeutics Committee (TC)
Pharmacy and therapeutics committee or the committee in
hospitals that evaluates the clinical use of drugs, develops
policies for managing drug use and drug administration;
manages the formulary system, and determines what
drugs will be available, at what cost, and how they will be
used
Unexpected adverse reaction
adverse reaction, the nature and severity of which is not
consistent with domestic labeling or market authorization,
or expected from the characteristics of the drug
Uppsala Monitoring Center (UMC)
WHO reporting center for adverse drug reactions where
reports are submitted and where global drug signals are
generated
-

NATIONAL PHARMACOVIGILANCE PROGRAM

integral part of Pre-Marketing and Post-Marketing
Surveillance of the FDA

National Pharmacovigilance
Program

EXERCISE 10

NPVAC
NPVC
RPVu
PhPVu
*annex 1: organizational chart
*annex 2: responsibilities

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NATIONAL
PHARMACOVIGILANCE
ADVISORY COMMITTEE
chaired by Director General of the
FDA and co-chaired by
Undersecretary for Regulation of
the DOH

NATIONAL
PHARMACOVIGILANCE
CENTER

Head

National Pharmacovigilance
Center shall serve as the
secretariat/member
Members with voting powers:
Chief National Epidemiology
Center
Chief (NCPAM)
Technical advisor/s
Program Managers NCDPC,
Expanded Program for
Immunization and the
Director of the HEMS
Chief Product Services
Division, FDA
Chief Legal Information and
Compliance Division, FDA
Chief NCHFD
ex-officio members with NO VOTING
power:
PMA
PCPM
PHA
PHAP
PHIC
BHFS
- authorized through a Department
Personnel Order
- Technical persons invited as resource
persons shall have no voting power

oversee the performance of the

National
Pharmacovigilance
Center and Pharmacovigilance
Units

review drug product safety update

recommend to FDA necessary

regulatory measures

recommend to the Secretary of

Health the involvement of other
parties who may be accredited to
perform activities that would
ensure the attainment of the
objectives

recommend to the FDA Director

General and the Secretary of
Health appropriate actions

have the appropriate

training on risk
management,
pharmacovigilance and
adverse drug reporting,
preferably a medical
doctor or one with an
M.S. degree in
Pharmacology or MS in
Clinical Pharmacy.

staff shall include the following:

3 clinical pharmacists

1 administrative
assistant

1 pharmacoepidemiologist/
biostatistician
- adequate training and resources in
pharmacology, biostatistics, risk
management, pharmacovigilance
and adverse drug reporting
- members have direct involvement
shall be profiled (assigned task,
previous and current, and their
credentials)
- maintain database of members of
different pharmacovigilance units
and changes/ amendments in the
composition of the members shall be
properly documented

REGIONAL
PHARMACOVIGILANCE
UNITS

RPVu shall be created in

every Center for
Health
Development
(CHDs)
teaching hospital
in the region
coordinator:
medical doctor
with adequate
training on
Pharmacovigilance
and risk
management
Doctors, pharmacists or
nurses trained in
Pharmacovigilance may
serve as staff.
Pharmacologist may serve
as consultant to assist the
unit.
- adequate training and
resources by the FDA
- Documentation shall be
required

PERIPHERAL
PHARMACOVIGILANCE
UNITS
Facility level

Shall include units from

medical
institutions,
medical centers,
individual medical
practitioners'
clinics, private
hospitals, nursing
homes,
pharmacies, public
facilities under the
local government
units, academic
institutions and
other government
agencies.
coordinator preferably be:
medical doctor
pharmacist
nurse with
adequate training
on
Pharmacovigilance
Other health care
professionals may serve as
staff.

FDANational Pharmacovigilance
Center: authority responsible for the
effective
implementation
and
coordination
of
the
National
Pharmacovigilance Program.

receive, encode and consolidate

all reports forwarded to the
ADR Unit
four important elements: patient,
suspected drug, adverse reaction and
reporter
develop regulatory instruments
create and maintain a database
establish intl collaboration
analyze collected reports and
make recommendations to FDA
sharing of safety information
between FDA and MAH
information to end-users
amend other functions
provide resources
recommend sanctions

Annex 2

Annex 2

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