© JMDM 2015

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 sub-

contracts, 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

Bureau of

Domestic Trade

(BDT)

partnership,

corporations

and other

juridical

persons

Certificate of

Registration

Securities and

Exchange

Commission

(SEC) and the

Articles of

Incorporation

of Partnership

Certificate of Registration of the

Establishment’s 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 BFAD-

Licensed 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

Drug Distributors

Importers 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.

Exporters Valid contract with BFAD licensed

manufacturer

Wholesalers valid contract with BFAD licensed

manufacturer, trader or distributor

certificate that products are registered with

BFAD

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.

Grounds for non-renewal of LTO:

Failure to comply

Serious, repeated or rampant violation

Persistent

Administrative Sanctions

Grounds for Revocation of LTO 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.

© JMDM 2015

Schedule of Fees

*Upon application for LTO, the following non-

refundable 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

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.

Pharmaceutical

Product

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 for

General Use

drug approved for sale to the

general public without restriction

other than the usual

Drug for

Restricted use

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 internationally-

recognized 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 category as

specified in the PNDF

*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.

© JMDM 2015

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

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.

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

© JMDM 2015

EXERCISE 10

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

*annex 1: organizational chart

*annex 2: responsibilities

Nat

ion

al P

har

mac

ovi

gila

nce

P

rogr

am

NPVAC

NPVC

RPVu

PhPVu

© JMDM 2015

NATIONAL

PHARMACOVIGILANCE

ADVISORY COMMITTEE

NATIONAL

PHARMACOVIGILANCE

CENTER

REGIONAL

PHARMACOVIGILANCE

UNITS

PERIPHERAL

PHARMACOVIGILANCE

UNITS

Facility level

chaired by Director General of the

FDA and co-chaired by

Undersecretary for Regulation of

the DOH

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

Head

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 pharmaco-

epidemiologist/

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

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

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.

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

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 int’l 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