drug approval system of the philippines

Drug Approval System of

the Philippines

Drafted Version (Expected to be revised)

May 2016

APEC Harmonization Center

- 1 -

Abbreviation

ACTD: ASEAN Common Technical Dossier

AO: Administrative Order

CDRR: Center for Drug Regulation and Research

CPR: Certificate of Product Registration

CSP: Compassionate Special Permit

DOH: Department of Health

DTN: Document Tracking Number

EO: Executive Order

ICH: International Council on Harmonisation

LOD: Letter of Disapproval

LTO: License to Operate

NOD: Notice of Deficiency

PAIR: Public Assistance, Information, and Receiving

RA: Republic Act

Notice

1. Due to the purpose of this document, most of the information was

quoted directly from the website or related guidelines of each

country’s drug regulatory agencies, and reviewed by the agencies.

2. This document is limited only to pharmaceutical products, not

applicable to biological and herbal products.

3. When referring to the contents of this document, check the up-to-

date information including related laws and regulations, and

revision of guidelines.

- 2 -

Table of Contents

I. Drug Regulatory Agency ···························································· 5

1. Food and Drug Administration···················································· 5

1.1 Organization·································································· 5

1.2 Tasks··········································································· 6

1.3 Contact Information························································· 8

II. Related Laws and Regulations······················································ 9

1. Republic Acts ······································································· 9

2. Related Regulations ································································ 9

III. Pharmaceutical Products and its Classification································ 10

1. New Drug··········································································· 11

2. Generic Drug······································································· 11

3. Orphan Drug········································································ 11

IV. Drug Approval System······························································ 12

1. Clinical Trial Application························································ 12

1.1 Establishments Authorized to Conduct Clinical Trial················· 12

1.2 Clinical Trial Application Requirements································ 13

1.3 Clinical Trial Approval Process·········································· 14

1.4 Amendment·································································· 14

1.5 Review Period······························································· 14

2. Drug Application and Registration·············································· 15

2.1 Overview····································································· 15

3. New Drug Application···························································· 16

3.1 Application Dossier························································ 17

3.2 Processing Timelines······················································· 19

4. Generic Drug Application························································ 20

4.1 Application Dossier························································ 20

4.2 Processing Timelines······················································· 21

5. Orphan drugs······································································· 21

- 3 -

6. Facilitated Applications··························································· 22

V. Others ·················································································· 23

1. Good Manufacturing Practice···················································· 23

1.1 GMP Inspection of Local Manufacturers······························· 23

1.2 GMP Clearance/Certificate of Foreign Manufacturers················ 23

2. Product Interchangeability························································ 23

2.1 Products Covered··························································· 26

2.2 BE Studies Conducted Abroad··········································· 26

2.3 Enforcement of Requirement············································· 26

3. Labeling Materials································································· 27

4. Certificate of Pharmaceutical Product ········································· 28

5. Renewal of Drug Registration··················································· 28

6. Post-Approval Changes ·························································· 29

6.1 Major Variation····························································· 29

6.2 Minor Variation – Prior Approval (MiV-PA) and Minor Variation –

Notification (MiV-N)······················································ 29

7. Fees ················································································· 30

VI. References·············································································· 32

- 4 -

List of Figures

Figure 1. Organization of the Food and Drug Administration

Figure 2. Overview of Drug Registration Process

List of Tables

Table 1. Comparison of ACTD and ICH CTD Documentation

Table 2. Documents Required for GMP Evidence Dossier

Table 3. Fees and Charges for LTO, CPR, Clinical Trials, Foreign GMP, and other

Certifications

List of Appendixes

Appendix 1. Organization of ACTD

Appendix 2. List of Molecules Requiring Proof of Interchangeablity

Appendix 3. Details on the Minimum Labeling Information

Appendix 4. List of Information Required per Labeling Material

Appendix 5. List of Post Approval Changes

- 5 -

I. Drug Regulatory Agency

1. Food and Drug Administration

As a regulatory agency under the Department of Health (DOH), the Food and Drug

Administration (FDA), created in 1963, is mandated to ensure the safety, efficacy or quality

of health products, which include food, drugs, cosmetics, devices, biologics, vaccines, in-

vitro diagnostic reagents, and household/urban hazardous substances and/or a combination of

and/or a derivative thereof. Also included are products that may have an effect on health,

which require regulations as determined by the FDA.

1.1 Organization

The FDA is comprised mainly by the following: the Internal Management Office, the

Field Regulatory Operations Office (FROO), four (4) centers according to product

jurisdiction, and the common services laboratory. Other main offices include the Policy and

Planning Service (PPS) and the Legal Service (LS).

Figure 1. Organization of the Food and Drug Administration1

1 As provided under Department Circular No. 2011-0101, “Implementing Rules and Regulations of R.A. No.

9711”, but with minor adjustments as recommended by the Department of Budget and Management (DBM)

- 6 -

1.2 Tasks

The tasks of the abovementioned offices are as follows:

1) Internal Management Office

develops plans and programs relative to finance and administrative management

determines and evaluates administration and finance risk management in

coordination with other offices within the FDA

coordinates with the Field Regulatory Operations Office (FROO) on matters

related to administration and finance

implements systems and procedures that will further enhance administration and

financial management

2) Field Regulatory Operations Office

supervision of all Regional Field Offices (RFOs), Laboratories and the Regulatory

Enforcement Units (REU);

recommend other government and private testing laboratories in the regions

qualified and properly equipped to conduct testing, calibration, assay, and

examination of samples and health products

implements systems and procedures that will further enhance field operations

management

3) The RFOs have the following functions:

implement laws, policies, plans, programs, rules and regulations of the FDA in the

regional area

administratively support the REU assigned in their respective region;

implement the postmarketing surveillance system in monitoring health products

and incidents of adverse events involving such products in coordination with the

PRSDD of each Center;

operate field and/or satellite laboratories in their respective regions;

inspect and evaluate establishments and issue appropriate renewal licenses, and

other appropriate authorizations as may be delegated and undertake compliance

monitoring;

evaluate health products and issue appropriate authorizations, as may be delegated

(except product registration) and undertake compliance monitoring;

coordinate with regional offices of other departments, bureaus and agencies in the

area;

coordinate with local government units in the area;

4) Policy and Planning Service

provides services on policy formulation, project development and evaluation,

research development and analysis, and coordination and monitoring

formulates, updates and conducts advocacy campaigns for appropriate legislation

on any matter relating to health products. PPS (i) coordinates with the executive

and legislative branches of the national government and other stakeholders on

- 7 -

matters and issues pertaining to regulation of health products and health product

establishments; (ii) manages the legislative, executive and other intergovernmental

liaison service support to the FDA and its different units or offices; and (iii)

monitors and reviews legislative and executive proposals on legislation of all

health products and health product establishments' regulation. PPS also coordinates

with the Legal Service (LS) and other Centers on technical matters pertaining to

legislation and regulation of health products and health product establishments

initiates, coordinates and implements the conduct of all relevant policy research

and development work, including maintenance of database of statistics related to

health products and supervises the collection, monitoring and publication thereof;

formulates and conducts advocacy, training and communication programs in

coordination with other government agencies, nongovernment and private entities

and sectors in furtherance of the mandate of the FDA

conducts integrated and performance-based planning and budgeting in consultation

with other offices

5) Legal Service

provides legal services to the entire FDA in the implementation of its mandate and

objectives

assists in the promulgation of rules governing the activities relating to the

operations of the FDA

coordinates with PPS in providing technical assistance and advisory services on

existing and proposed legislation and regulation on health products and health

products establishment

6) Common Services Laboratory

analyzes and inspects health products

establishes analytical data to serve as basis for the preparation of health products

standards, and to recommend standards of identity, purity, safety, efficacy, quality

and fill of container

conducts appropriate tests on all applicable health products prior to the issuance of

appropriate authorizations

audits centers conducting bioavailability and bioequivalence tests, as may be

delegated

accredits private testing laboratories

7) Centers

regulate the manufacture, importation, exportation, distribution, sale, offer for sale,

transfer, promotion, advertisement, sponsorship of, and/or, where appropriate, the

use and testing of health products

conduct research on the safety, efficacy, and quality of health products

institute standards for the safety, efficacy, and quality of health products

inspect and evaluate establishments covered by the particular Center and issue

appropriate licenses;

- 8 -

evaluate and issue appropriate authorizations for all health products and health

product establishments regulated by each Center

conduct PMS on health products;

employ a consultative risk management approach to decision-making across all

product classes;

provide technical assistance, consultative and advisory services to stakeholders and

other government agencies in the implementation of laws, rules and regulations

pertaining to health products

1.3 Contact Information

Website: www.fda.gov.ph

Email: [email protected], [email protected]

Phone: +63 2 857 1900

Social Media: www.facebook.com/FDAPhilippines

http://www.fda.gov.ph/

mailto:[email protected]

mailto:[email protected]

- 9 -

II. Related Laws and Regulations

1. Republic Acts2

In the regulation of drug products, the FDA is guided mainly by under Republic Act (RA)

3720, series of 1963, as amended by EO 175, series of 1987, otherwise known as the “Food,

Drugs and Devices, and Cosmetics Act”, and subsequently RA 9711 otherwise known as

“The Food and Drug Administration Act of 2009:.

The FDA is also guided by the following RA:

RA 3720, Food, Drugs and Devices, and Cosmetics Act

RA 9711, Food and Drug Administration (FDA) Act of 2009

RA 5921, Pharmacy Law

RA 6675, The Generics Act of 1988

RA 7394, Consumer Act of the Philippines

RA 8203, Special Law on Counterfeit Drugs

RA 9165, Comprehensive Dangerous Drugs Act of 2002

RA 9502, Universally Accessible Cheaper Quality Medicines Act of 2008

RA 10352, Philippine National Health Research System Act of 2013

RA 10354, The Responsible Parenthood and Reproductive Health Act of 2013

RA 10747, Rare Diseases Act of the Philippines

2. Related Regulations

As a policy and standard setting body, regulatory requirements are provided in the

following issuances:

Executive Orders3

Administrative Orders4

FDA Circulars5

FDA Memorandum Circulars6

2 http://www.fda.gov.ph/issuances-2/pharml-1/pharml-republic-act

3 http://www.fda.gov.ph/issuances-2/pharml-1/pharml-executive-order

4 http://www.fda.gov.ph/issuances-2/pharml-1/pharml-administrative-order

5 http://www.fda.gov.ph/issuances-2/pharml-1/pharml-fda-circular

6 http://www.fda.gov.ph/issuances-2/pharml-1/pharml-memorandum-circular

- 10 -

III. Pharmaceutical Products and its Classification

Pharmaceutical product, drug, drug product or finished pharmaceutical product refers to:

1) any article recognized in the official United States Pharmacopoeia-National

Formulary (USP-NF), official Homeopathic Pharmacopoeia of the United States,

Philippine Pharmacopoeia, Philippine National Drug Formulary, British

Pharmacopoeia, European Pharmacopoeia, Japanese Pharmacopoeia, Indian

Pharmacopoeia, any national compendium or any supplement to any of them;

2) any article intended for use in the diagnosis, cure, mitigation, treatment or prevention

of disease in humans or animals;

3) any article other than food intended to affect the structure or any function of the

human body or animals;

4) any article intended for use as a component of any articles specified in clauses (1), (2)

and (3) not including devices or their components, parts or accessories;

5) herbal and/or traditional drugs which are articles of plant or animal origin used in folk

medicine which are:

(a) recognized in the Philippine National Drug Formulary

(b) intended for use in the treatment or cure or mitigation of disease symptoms,

injury or body defects in humans

(c) other than food, intended to affect the structure or any function of the human

body

(d) in finished or ready-to-use dosage form; and

(e) intended for use as a component of any of the articles specified in clauses (a), (b),

(c) and (d).

In the Philippines, drug products are classified into the following:

1) New Drugs or New Chemical Entities

2) Biological Products

3) Generic Drugs

4) Traditionally-Used Herbal Products

5) Herbal Medicines

6) Household Remedies

7) Over-the-Counter Preparations

8) Veterinary Drugs

9) Medical Gases

10) Stem Cell Products

For Purposes of this paper, the following shall be covered:

- 11 -

1. New Drugs7

New drug or new chemical entity (NCE) refers to a product previously authorized for

marketing in any pharmaceutical use in the Philippines. It may refer to:

1) Any drug the composition of which is such that said drug is not generally recognized

among experts qualified by scientific training and experience to evaluate the safety,

efficacy, and quality of drugs as safe, efficacious and of good quality for use under the

conditions prescribed, recommended, or suggested in the labelling thereof.

2) Any drug the composition of which is such that said drug, as a result of previous

investigations to determine its safety, efficacy and good quality for use under certain

conditions, has become so recognized but which has not, otherwise than in such

investigations, been used to a material extent or for a material time under new

conditions.

3) "New drugs" shall include drugs:

(a) containing a newly discovered active ingredient

(b) containing a new fixed combination of drugs, either by molecular or physical

combination

(c) intended for new indications

(d) in an additional new mode of administration;

(e) in an additional dosage of strength of the dosage form, which meets the conditions

as defined under the new drug.

New drugs are registered under monitored-release status.

2. Generic drugs8

Generic drug is a product considered to be essentially similar or bioequivalent to a

reference drug. These are drugs that are pharmaceutically equivalent but may or may not be

therapeutically equivalent, and are not covered by patent protection and which are labeled

solely by their international non-proprietary name or generic name.

3. Orphan drugs9

Orphan drug refers to any drug or medicine used to treat or alleviate the symptoms of

persons afflicted with a rare disease and declared as such by the DOH upon recommendation

of the National Institutes of Health (NIH).

7 Executive Order No. 175, “Further Amending Republic Act No. 3720, Entitled “An Act to Ensure the Safety

and Purity of Foods, Drugs, and Cosmetics Being Made Available to the Public by Creating the Food and Drug

Administration which shall Administer and Enforce the Laws Pertaining thereto”, as Amended, and for Other

Purposes” 8 Definition from the following: Republic Act No. 6675, “Generics Act of 1988”, and ACTD Glossary, as

adopted by Administrative Order No. 2013-00021 9 Republic Act No. 10747, “Rare Disease Act of the Philippines”

- 12 -

IV. Drug Approval System

1. Clinical Trial Application

The FDA is mandated to conduct, supervise, monitor and audit research studies on health

and safety issues of health products undertaken by duly authorized by the FDA10

. All clinical

trials to be conducted in the Philippines need to secure approval of their protocol prior to the

conduct, which is required per phase of the trial.11

Clinical trial is defined by the FDA as any investigation in human subjects intended to

discover or verify the clinical, pharmacological and/or other pharmacodynamics effects of an

investigational product(s) (IP), and/or to identify any adverse reactions to an investigational

product(s), and/or to study absorption, distribution, metabolism, and excretion of an

investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms

clinical trial and clinical study are synonymous12

. Investigational new drug (IND) or

investigational product refers to a pharmaceutical form of an active ingredient or placebo

being tested or used as a reference in a clinical trial, including a product with a marketing

authorization when used or assembled (formulated or packaged) in a way different from the

approved form, or when used for an unapproved indication, or when used to gain further

information about an approved use. The definitions were adopted from the International

Council for Harmonisation (ICH) (previously International Conference on Harmonisation)

guideline on Good Clinical Practice (GCP)13

.

In the conduct of clinical trial, strict adherence to GCP, good laboratory practice, and other

best practices is required, including full disclosure of all pertinent documentation during

application and inspection.14

1.1 Establishments Authorized to Conduct Clinical Trial

Establishments authorized by the FDA include Sponsors and Clinical Research

Organizations (CROs)15

. The FDA issues a License to Operate (LTO) as proof of

authorization for these establishments.

Sponsor is defined as an individual, company, institution, organization or an entity which

takes the responsibility for the initiation, management, and/or financing of a clinical trial.

CRO, on the other hand, is defined as a person or an organization (commercial, academic,

or other) contracted by the sponsor to perform one or more of the sponsor’s trial-related

duties and functions. As long as the CRO engages in any of the following activities as

delegated by the sponsor, LTO is required:

10

Section 5 (n) of RA 9711 11

Administrative Order No. 47-a s. 2001, Rules and Regulations on the Registration, including Approval and

Conduct of Clinical Trials, and Lot or Batch Release Certification of Vaccines and Biologic Products 12

Administrative Order No. 2014-0034, Rules and Regulations on the Licensing of Establishments Engaged in

the Manufacture, Conduct of Clinical Trial, Distribution, Importation, Exportation, and Retailing of Drug

Products, and Issuance of Other Related Authorizations 13

ICH Harmonised Tripartite Guideline, Guideline for Good Clinical Practice E6(R1) 14

FDA conducts postlicensing inspection 15

FDA Circular No. 2015-003, Guidelines on the Implementation of New Rules and Regulations on the

Licensing of Sponsors and Contract Research Organizations (CROs) following Administrative Order No. 2014-

0034, dated 13 October, 2014

- 13 -

1) Oversight (e.g. ensuring quality assurance and/or quality control systems are in place

to ensure clinical trials are conducted, data is gathered, and subsequently reported)

2) Management of clinical trials

development of protocols and/or trial design;

selection of investigator(s) and/or site(s);

screening and/or recruitment of subjects;

data handling (e.g. collection, analysis/evaluation, and record keeping)

Entities involved in the procurement/importation, storage, and/or distribution of

investigational product(s) are not required to secure an LTO as CRO, unless they are

involved in other activities mentioned above. These entities must follow other existing

licensing requirements.

1.2 Clinical Trial Application Requirements

A clinical trial dossier is required, consisting of the following documents:

Part A: Clinical Trial Protocol and other documents

1) Name and dosage form of product

2) Title and aim of the trial; Description of the trial design

3) Treatment profile; Operational aspects

4) Adverse events

5) Evaluation of results

6) Informed consent form, case report form and patient information sheet

7) Resumes of principal and other investigators

8) For multicentre studies, a list of principal investigators with contact details (and CVs)

including trial sites

Part B: Pharmaceutical Data

1) GMP statement from manufacturing/Certificate from Regulatory Body

2) Certificate of Analysis

3) Stability Data (storage conditions)

4) Manufacturing Data and Formulation

5) Product labelling (coded and labelled: blinding)

Part C: Investigator’s brochure (Efficacy and Safety data)

1) Safety data:

a. Non-clinical studies; Toxicology studies

b. Pharmacology: PK/PD studies

c. Marketing experience, Periodic Safety Update Reports (PSUR), product status if

marketed abroad

d. Risks and ADR anticipated

2) Efficacy data:

a. PK/PD data in human subjects;

b. In-house preliminary data

- 14 -

c. Summaries of clinical trial studies conducted (Phase I,II,III)

d. Published clinical data

1.3 Clinical Trial Approval Process

Application begins upon submission of the clinical trial dossier through the of an

electronic copy application at the Public Assistance, Information, and Receiving (PAIR)

without the need for appointment16

.

Once an applicant submits the dossier, CDRR evaluates the documents and determines if:

Study has scientific value and worth pursuing/conducting

Conducted by duly licensed establishments

Compliant with GCP, and other applicable best practices

Compliance to safety and efficacy standards of ICH17

If the protocol is found to be acceptable, a Clinical Trial Protocol Approval is issued by

the FDA and gives instructions to the applicant to apply for Import Permit for Clinical Trials

to access imported INDs, including ancillary supplies such as laboratory kits, reagents, and

other materials to be used for the clinical trial18

.

1.4 Amendment

If, during the conduct of the clinical trial, changes in the protocol are necessary,

appropriate amendments should be submitted to the FDA seeking approval.

1.5 Review Period

A maximum of 90 calendar days is given by the FDA in the processing of clinical trial

approval applications; for amendment, 60 calendar days; and for import permit, 30 calendar

days.

16

FDA Circular No. 2014-009, Filing and Submission of Applications for the Approval of Clinical Trial

Protocol, Compassionate Special Permit (CSP), Import Permit for Investigational Drug Products,

Pharmacovigilance, Adverse Events/Adverse Reaction Reports, and other related documents 17

FDA Circular No. 2013-019, Adoption of the International Conference on Harmonisation (ICH) Safety and

Efficacy Guidelines 18

FDA Circular No. 2012-007, Recognition of Ethical Review Board/Committee (ERB/ERC) for Purposes of

the Conduct of Clinical Trials on Investigational Medicinal Products in the Philippines and for Other Purposes

- 15 -

2. Drug Application and Registration

2.1 Overview

For a company to be able to market a drug product in the Philippines, securing a

marketing authorization in the form of a Certificate of Product Registration (CPR) is

necessary. A CPR covering a particular drug product shall be a prima facie evidence of the

registrant's marketing authority for the said drug product in connection with the activities

permitted pursuant to the issuance of a LTO. The figure below generally describes the process

of registration.

Figure 2. Overview of Drug Registration Process

The process above generally describes the process of registration. The process begins with

the submission of an electronic copy application using the Integrated Application Form at the

Submission

Evaluation

With

deficiencies?

Issuance of CPR NOD/LOD

Releasing

No Yes

- 16 -

PAIR, by appointment schedule19

of an applicant company (which may be a licensed

manufacturer, trader, or distributor).

Once an applicant submits the dossier, CDRR evaluates the documents and determines if

the product meets the standards of safety, efficacy, and quality. If the product meets these

standards, a CPR is issued valid for five (5) years. Should deficiencies be noted, depending

on the criticality, a Notice of Deficiency (NOD) or Letter of Disapproval (LOD) may be

issued.

The FDA disapproves products based on the following grounds20

:

The application requirements submitted show that the drug product does not meet the

required technical requirements or appropriate standards;

The applicant made misrepresentations, false entries, or withheld any relevant data;

Major inconsistencies in the information provided in the registration dossier;

Major queries that were not clarified or addressed satisfactorily by the applicant

company in the compliance for NOD; and

Major inconsistencies in the compliance for NOD and the registration dossier.

3. New Drug Application

In 1 July 2013, the FDA adopted the Association of Southeast Asian Nations (ASEAN)

Common Technical Dossier (ACTD) and Common Technical Requirements (ACTR) for the

registration of pharmaceutical products for human use21

. The ACTD is a product of the

tireless efforts of the ten ASEAN Member States’ (AMS) drug regulatory authorities (DRAs)

conducting consultative meetings through the ASEAN Consultative Committee for Standards

and Quality (ACCSQ) – Pharmaceutical Product Working Group (ACCSQ-PPWG). The

objective of the ACCSQ-PPWG is to develop harmonized schemes in pharmaceutical product

regulation acceptable to ASEAN DRAs.

The ACTD, which is defined as the part of marketing authorization application dossier

common to all AMS, covered (1) new drugs or NCEs, (2) prescription generic drug products,

and biological products. ACTR, a set of written materials intended to guide applicants to

prepare application dossiers in a way that is consistent with the expectations of all ASEAN

DRAs, consists of the following guidelines:

ASEAN Guidelines on Stability Study of Drug Product

ASEAN Guidelines on Submission of Manufacturing Process Validation Data for

Drug Registration

ASEAN Guidelines for Validation of Analytical Procedures

ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies

ASEAN Guidelines on Nonclinical (Safety) Document

ASEAN Guidelines on Clinical (Efficacy) Document

ASEAN Variation Guidelines for Pharmaceutical Products

19

FDA Circular No. 2014-00, “Filing and Receiving of Registration, Licensing and Other Application Using

the Integrated Application Form” 20

As provided under the IRR of RA 9711 21

Administrative Order No. 2013-0021, “Association of Southeast Asian Nations (ASEAN) Common

Technical Dossier (ACTD) and Common Technical Requirements (ACTR) for the registration of pharmaceutical

products for human use”

- 17 -

The FDA also allows flexibilities of submission for products following the ICH Common

Technical Document (ICH CTD) format, but following specific requirements acceptable to

ASEAN (e.g. Stability requirements)22

. The table below describes the flexibilities between

ACTD and ICH CTD.

Documents Location

ACTD ICH CTD

Administrative Documents

and Product Information

Part I Module 1

Common Technical

Document Overview and

Summaries

Incorporated in Parts II, III,

and IV

Module 2

Quality Documents Part II Module 3

Non-Clinical Documents Part III Module 4

Clinical Documents Part IV Module 5

Table 1. Comparison of ACTD and ICH CTD Documentation

3.1 Application Dossier

As new drugs are covered by ACTD, the required documents23

are as follows:

Part I: Administrative Data and Product Information

1) Section A: Introduction

2) Section B: Table of Contents

3) Section C: Guidance on the Administrative Data and Product Information

a. Integrated Application Form

b. Letter of Authorization (where applicable)

c. Certifications

d. Labeling

e. Product Information

Part II: Quality

1) Section A: Table of Contents

2) Section B: Quality Overall Summary

3) Section C: Body of Data

Drug Substance

a. General Information

b. Manufacture

c. Characterization

d. Control of Drug Substance

e. Reference Standards or Materials

22

FDA Circular No. 2013-019, “Organization of the ASEAN Common Technical Dossier (ACTD) for the

Registration of Pharmaceutical Products for Human Use” 23

Guidance for each document is provided under the ACTD Guidance Document available at

http://www.fda.gov.ph/industry-corner/downloadables/217-requirements-for-drug-registration

- 18 -

f. Container Closure System

g. Stability

Drug Product

a. Description and Composition

b. Pharmaceutical Development

c. Manufacture

d. Control of Excipients

e. Control of Finished Product

f. Reference Standards or Materials

g. Container Closure System

h. Product Stability

Part III: Nonclinical Document


2) Section B: Nonclinical Overview

3) Section C: Nonclinical Written and Tabulated Summaries

a. Nonclinical Written Summaries

b. Content of Nonclinical Written and Tabulated Summaries

c. Nonclinical Tabulated Summaries

4) Section D: Nonclinical Study Reports

a. Table of Contents

b. Pharmacology

c. Pharmacokinetics

d. Toxicology

5) Section E: List of Key Literature References

Part IV: Clinical Document


2) Section B: Clinical Overview

3) Section C: Clinical Summary

a. Summary of Biopharmaceutic Studies and Associated Analytical Method

b. Summary of Clinical Pharmacology Studies

c. Summary of Clinical Efficacy

d. Summary of Clinical Safety

e. Synopses of Individual Studies

4) Section D: Tabular Listing of All Clinical Studies

5) Section E: Clinical Study Reports (if applicable)

a. Reports of Biopharmaceutic Studies

b. Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials

c. Reports of Human Pharmacokinetic (PK) Studies

d. Reports of Human Pharmacodynamic (PD) Studies

e. Reports of Efficacy and Safety Studies

f. Reports of Post-Marketing Experience

g. Case Report Forms and Individual Patient Listing

- 19 -

6) Section F: List of Key Literature References

Country specific requirement include submission of foreign GMP Clearance24

for

imported products.

The organization of ACTD including its subsections is attached as Appendix 1.

3.2 Processing Timelines

A maximum of 254 calendar days is given by the FDA in the processing of initial

applications for new drugs, excluding stop-clocks due to noted deficiencies.25

24

Administrative Order No. 2013-0022, “Guidelines for Current Good Manufacturing Practice (cGMP)

Clearance and Inspection of Foreign Drug Manufacturers” 25

CDRR’s Citizen Charter for the processing of initial applications as provided at

http://www.fda.gov.ph/issuances-2/cosmetic-laws-and-regulations-pertaining-to-all-regulated-cosmetic-

products/cosmetic-memorandum-circular/226409-fda-citizen-s-charter-cdrr-2

- 20 -

4. Generic drug approval application

4.1 Application Dossier

The requirements for generic drug registration depend on the dispensing category of the

products. For prescription products, application dossier is based on ACTD:


1) Section A: Introduction

2) Section B: Table of Contents

3) Section C: Guidance on the Administrative Data and Product Information

a. Integrated Application Form

b. Letter of Authorization (where applicable)

c. Certifications

d. Labeling

e. Product Information

Part II: Quality


2) Section B: Quality Overall Summary

3) Section C: Body of Data

Drug Substance

a. General Information

b. Manufacture

c. Characterization

d. Control of Drug Substance

e. Reference Standards or Materials

f. Stability

Drug Product

a. Description and Composition

b. Pharmaceutical Development

c. Manufacture

d. Control of Excipients

e. Control of Finished Product

f. Reference Standards or Materials

g. Container Closure System

h. Product Stability

i. Product Interchangeability

For over-the-counter (OTC) preparations and household remedy (HR) products,

application dossier is based on national guidelines:

Integrated Application Form

Valid agreements between the manufacturer, trader, importer, distributor, where

applicable

- 21 -

Unit Dose and Batch Formulation

Technical Specifications of all Raw Materials

Certificate of Analysis of active Raw Material(s)

- From supplier of API

- From manufacturer of finished product

Technical Specifications of Finished Product

Certificate of Analysis (CA) of Finished Product (from the same batch of

representative sample)

Manufacturing Procedure, Production Equipment, Sampling, In-process controls, and

Master Packaging Procedure (including specification for container closure system)

Assay and Other Test Procedures including Identity, Purity Tests, with Data Analysis,

where applicable

Stability Studies

Labeling Materials (facsimile labels)

Product Interchangeability

Country specific requirement for both include submission of foreign GMP Clearance for

imported products.

4.2 Processing Timelines

A maximum of 254 calendar days is given by the FDA in the processing of initial

applications for generic drug products, excluding stop-clocks due to noted deficiencies.

5. Orphan drugs

Orphan drugs are registered following a facilitated registration process and may fall either

through the abovementioned categories (or as biological preparations), or may be accessed by

patients using a Compassionate Special Permit (CSP). A CSP is a special permit signed by

the FDA Director granting a Specialized Institution (SI) and Specialty Society (SS) the

privilege to avail of an unregistered drug and device product through a certain licensed

establishment for certain kind/type of patients, specific volume and period. Patients having

the following conditions are allowed to use CSP:

1) Acquired Immune Deficiency Syndrome (AIDS)

2) Cancer

3) Life-threatening conditions

The requirements for securing a CSP are the following:

1) Letter of Application

2) Name and contact details of Specialist of the patient

3) Prescription

4) Medical Abstract of Patient

A maximum of 15 calendar days is given by the FDA in the processing of CSP.

- 22 -

6. Facilitated Applications26

The FDA provides a facilitated registration of applications following certain categories:

1) Products to be manufactured exclusively for export

2) New drug products considered to be a major therapeutic advance

3) The first 5 products of newly licensed establishments without any registered drug

product yet to its name

4) Products for government programs and projects

5) Imported prequalified vaccines

A maximum of 90 calendar days is given by the FDA for facilitated applications,

excluding stop-clocks due to noted deficiencies.

26

CDRR Memorandum No.: 0003, Series 2013, Facilitation of Applications for Product Registration

- 23 -

V. Others

1. Good Manufacturing Practice

In the Philippines, the standard of Good Manufacturing Practice (GMP) is the

Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme

(PIC/S-GMP)27

.

Once an application for GMP clearance/certificate is received by the FDA, whether (1)

part of securing a License to Operate (LTO) of a local manufacturer, or (2) prior to

registration of a product from a foreign manufacturer, CDRR and FROO assesses the GMP

compliance of a manufacturer through desktop review and, where applicable, inspection.

PIC/S-GMP consists of the following elements:

Quality Management

Personnel

Premises and Equipment

Documentation

Production

Quality Control

Contract Manufacture and Analysis

Complaints and Product Recall

Self-Inspection

Compliance to GMP is mandatory prior to registration of any drug product.

1.1 GMP Inspection of Local Manufacturers

All local establishments desiring to engage in the manufacture, distribution, importation,

exportation, sale, offer for sale and transfer of any drug product, must first secure an LTO,

which serves as the establishment’s compliance to the required standard of good practice. For

manufacturer’s, compliance to GMP is required and is proved and continuously monitored

during inspection.

1.2 GMP Clearance/Certificate of Foreign Manufacturers

As with local manufacturers, foreign drug manufacturers must prove compliance to

GMP. However, in consideration of the GMP evidences of foreign manufacturers as applied

by select countries, the FDA has opened the opportunity to prove GMP compliance only

through desktop evaluation.

1.2.1 Documentation

The following documents are required upfront upon application:

Letter of Request

Foreign GMP Application Form

27

Administrative Order No. 2012-0008, “Adoption and Implementation of the Pharmaceutical Inspection

Cooperation Scheme (PIC/S) Guides for the Good Manufacturing Practice (GMP) for Medicinal Products”

- 24 -

GMP Evidence

GMP Evidence Dossier (required for Non-PIC/S countries)

Affidavit of Undertaking

GMP evidence may either be:

GMP Certificate (Certificate of GMP Compliance); or

WHO Certificate of a Pharmaceutical Product; or

Manufacturer's License or Manufacturing Authorization incorporating the specific

medicinal product(s)/dosage form(s)

For those manufacturers not coming from a PIC/S member country, a GMP evidence

dossier is required to be submitted, which consists of documents depending on the

manufacturing steps the said establishment engages with:

Documents Required Manufacturing Steps

Full

Manufacture

Bulk

Manufacture QC Testing

Packaging /

Labeling

Release for

supply Sterilization

An original or notarized

copy of a GMP certificate

A copy of the last

inspection report and the

manufacturer’s response

to any deficiencies noted

A copy of the GMP

contract between the

manufacturer and the

Importer, including a list

of the specific products

for supply in the

Philippines.

A copy of the Site Master

File or equivalent

A copy of the Validation

Master Plan (covering

process, media fill (if

relevant), cleaning,

computerized systems, etc

as applicable and

including a Risk

Assessment used to

determine the scope and

extent of validation)

Rationale for test method

validation, procedure for

method transfer etc.

Copies of the procedures

for handling deviations

and out of specification

test results

Table 2. Documents Required for GMP Evidence Dossier

- 25 -

1.2.2 Process

The process of foreign GMP clearance begins with the submission of application by the

licensed local importer. Upon receipt of application, CDRR evaluates and determines

compliance of the establishment with the required standards of GMP. If the foreign

manufacturer has been inspected by a PIC/S-member country, inspection will no longer be

required; otherwise, the RFO evaluates the GMP evidence in preparation for the inspection.

Logistical preparations for inspection are coordinated with the applicant importer28

. As part

of the commitment to transparency, the FDA publishes in the FDA website the list of foreign

manufacturers subject to inspection.29

If upon desktop evaluation it was found that the manufacturing site is compliant to GMP,

CDRR shall issue a GMP Clearance with validity similar to the evidence presented; if after

inspection it was found that the manufacturing site is compliant to GMP, FROO shall forward

to CDRR the results of inspection and recommendation to issue a GMP Certificate. The list of

foreign manufacturers compliant to GMP is also published in the FDA website.30

1.2.3 Review Period

For foreign manufacturers not requiring inspection: 15-21 working days; for foreign

manufacturers requiring inspection: 45-60 working days, exclusive of inspection.

2. Product Interchangeability

In line with the mandate of the Food and Drug Administration of ensuring the availability

of safe, efficacious and quality pharmaceutical products in the Philippines, the FDA

introduced the concept of Bioavailability/Bioequivalence to all stakeholders, highlight the

importance of establishing interchangeability between innovator (originator) and multisource

(generic) pharmaceutical products, and correspondingly require the submission of satisfactory

BA/BE as early 199731

.

However, due to the unavailability of Philippine-based testing facilities and/or

bioanalytical test methods used in the conduct of the studies then, a selective moratorium on

this requirement was imposed. After several years, in 201332

, the FDA was able to fully

implement the requirement of BE.

28

FDA Circular No. 2014-016, “Implementing Guidelines for Administrative Order No. 2013-0022 dated 13

August 2013, Subject: Guidelines for Current Good Manufacturing Practice (cGMP) Clearance and Inspection

of Foreign Drug Manufacturers” 29

http://www.fda.gov.ph/industry-corner/list-of-foreign-manufacturers-for-foreign-inspection 30

http://www.fda.gov.ph/industry-corner/list-of-manufacturing-site-with-gmp-clearance 31

Bureau Circular No. 01 s. 1997, Enforcement of the Requirement for Bioavailability Studies for Registration

of Products Included in the List B' (Prime) under Administrative Order No. 67 s. 1989 were issued to Study

Reports 32

FDA Circular No. 2013-014, “List of Products Requiring Bioequivalence (BE) Studies as part of the

Application Marketing Authorization in Addition to Rifampicin and the 11 Products Listed in Bureau Circular

No. 2006-008”

- 26 -

2.1 Products Covered

2.1.1 Products Requiring the submission of satisfactory BE Study Reports

1) Class 4 drugs (low solubility, low permeability) based on the revised World Health

Organization (WHO) criteria for Biopharmaceutics Classification Systems (BCS)

2) Class 2 drugs (high permeability, low solubility) not eligible for biowaiver based on

the revised WHO criteria for BCS

3) Subsequent generic products to be marketed after the patent expiration of the

innovator: Principle: The innovator drug has proven its safety and efficacy in view of

available satisfactory clinical data/studies. When its patent expires, pharmaceutical

manufacturers may produce generic versions of the innovator products, provided they

can establish product interchangeability through BE Studies or Biowaiver, whichever

is applicable.

4) All modified-release pharmaceutical products for oral administration designed to act

systemically.

2.1.2 Products that may avail of Biowaiver provided they meet all applicable

WHO criteria for application of the Biowaiver procedure (including certain

products covered in Bureau Circular No. 2006-008)

1) Class 1 drugs (high permeability, high solubility) based on the revised WHO criteria

for BCS

2) Class 2 drugs (high permeability, low solubility) with weak acidic properties based on


3) Class 3 drugs (low permeability, low solubility) based on the revised WHO criteria

for BCS

The list of molecules covered by the requirement is attached as Appendix 2 This list is not

exhaustive and may be changed from time to time.

2.2 BE Studies Conducted Abroad

Following the ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence

Studies, the FDA allows the submission of BE study reports conducted abroad so long as the

following are satisfied:

All BE Study Reports shall be accompanied by a copy of the valid Certificate of

Accreditation of the foreign BA/BE testing center which conducted the study, issued

by the governing regulatory authority or in its absence, an independent accrediting

body. The BA/BE testing center's accreditation shall be based on satisfactory

compliance with Good Clinical Practice (GCP) and Good Laboratory Practice (GLP)

principles.

The reference drug (comparator) shall be determined by the FDA. Generally, this is

the innovator drug registered and marketed in the Philippines. If there is no reference

- 27 -

drug, either a leading product in the market or the generic drug product(s) registered

after the innovator may serve as the alternative to reference drug.

If a study has already used the same reference drug recognized by the FDA, but of a

different manufacturer or manufacturing site, a multi-comparative dissolution profile

between reference drugs from 2 different manufacturers/manufacturing sites shall be

provided together with the BE Study Report. The test shall be performed according to

the WHO guideline for in vitro test (e.g. using pH 1.2 HCl solution, pH 4.5 acetate

buffer, and pH 6.8 phosphate buffer in immediate-release oral dosage forms).

Report Format: The BE Study Report shall follow the ASEAN Bioequivalence Study

Reporting Format

2.3 Enforcement of Requirement

BE requirement for BCS class 4 drugs took effect last 1 July 2013, expanded to other

products beginning 1 January 2014. For existing products, the FDA gave a conditional

approval of 2 years to complete the requirement; however starting 01 July 2016 full

implementation will begin which mean failure to comply shall result in recall and

cancellation of existing CPR.

3. Labeling Materials

In 1988, RA 6675 was enacted which required the use of generic terminology for drug

products. This led the Philippines to be one of the first few countries to implement a generic

labeling33

concept, emphasizing on the generic name of the product rather than its brand or

trade name. In March 2016, the revised rules and regulations for labeling requirements was

issued34

, which is aligned with the requirements of ASEAN.

The minimum mandatory requirements include:

1) Product Name

2) Dosage Form and Strength

3) Pharmacologic Category

4) Formulation/Composition

5) Indication(s)

6) Dosage and Mode of Administration

7) Contraindication(s), Precaution(s), Warning(s) (if applicable)

8) Interactions

9) Adverse Drug Reaction(s)

10) Overdose and Treatment

11) Storage Condition(s)

12) Net Content or Pack Size

13) Name and Address of MAH

14) Name and Address of Manufacturer

33

One of the earliest to implement generic labelling concept through Administrative Order No. 55 s. 1988,

“Requirements for Labeling Materials of Pharmaceutical Products” 34

Administrative Order No. 2016-0008, Revised Rules and Regulations Governing the Generic Labeling

Requirements of Drug Products for Human Use

- 28 -

15) For prescription drug products, Rx Symbol and Caution Statement

16) ADR Reporting Statement

17) Registration Number

18) Batch Number and Lot Number (if any)

19) Expiration Date and Date of Manufacture

Details of the abovementioned minimum information required are attached as Appendix 3,

while the content per labeling requirement is attached as Appendix 4.

4. Certificate of Pharmaceutical Product

The Certificate of Pharmaceutical Product (CPP) describes the registration status of a

pharmaceutical product in the Philippines. It also certifies that the manufacturing plant in

which the product is produced undergoes periodic inspection and that it conforms to the

requirements of GMP.

CDRR issues a CPP to applicant companies who are planning to export a pharmaceutical

product as may be required by the drug regulatory authority of the importing country. The

CPP may be required by the importing country during the first importation and subsequently

if confirmation or updating is required. The requirements for the issuance of CPP are the

following:

1) Request letter with importing country

2) Copy of CPR and LTO of MAH

3) Immediate and secondary labeling materials

4) Unit Dose Formulation

5. Renewal of Drug Registration

CPRs issued by the FDA are given 5 year validity. For continuous marketing authorization

after the validity, the MAH shall apply for renewal of registration. Submission of the

application for renewal shall be on or 120 days before the expiration date of the CPR.

Renewal shall be accepted unless the prescribed renewal fee is paid.

There shall be automatic renewal of the CPR when the following conditions are satisfied:

The application is filed before the expiration date of the registration;

The prescribed renewal fee is paid upon filing of the application; and

A sworn statement indicating no change or variation whatsoever in the product is

attached to the application.

For applications filed from within 120 days from its original expiry, the CPR shall be

considered valid and existing until a decision or resolution by the FDA is rendered on the

application for renewal.

Failure to market a pharmaceutical product, without legitimate reason, during an

uninterrupted period of at least 3 years from the date of issuance or renewal of the registration

or the last date of operation or marketing shall be a ground for cancellation of CPR.

Failure to apply for renewal registration shall mean cancellation of the CPR. If the

company wishes to reapply for renewal, then the corresponding surcharge will apply.

- 29 -

6. Post-approval Changes

It is understood that throughout the life cycle of a drug product, changes may occur on the

administrative and technical details in the registration dossier which may affect the safety,

efficacy, and quality of the product. In line with this, the product owner must seek approval

from the FDA to implement the change or provide notification depending on the type of

variation being proposed.

In the post-approval change (PAC) scheme of the FDA35

, changes are classified either as

those falling under the ASEAN Variation Guidelines for Pharmaceutical Products, or those

falling under country specific requirements. PACs are also classified according to the risk

associated with the product:

6.1 Major Variation

This refers to a variation to a registered pharmaceutical finished product that may affect

significantly and/or directly the aspects of quality, safety and efficacy and it does not fall

within the definition of minor variation and new registration.

6.2 Minor Variation – Prior Approval (MiV-PA) and Minor Variation –

Notification (MiV-N)

This refers to a variation to a registered pharmaceutical finished product in terms of

administrative data and/or changes with minimal/no significant impact on the aspects of

efficacy, quality, and safety.

The list of PACs falling under each category is attached as Appendix 5.

35

FDA Circular No. 2014-008, Application Process and Requirements for Post-approval Changes of

Pharmaceutical Products

- 30 -

7. Fees

In 2001, the FDA issued its schedule of fees and charges36

. As new requirements are

issued, separate fees are included. The table below summarizes the fees for the applications

covered in this document, exclusive of Legal Research Fee (LRF)37

.

LICENSE TO OPERATE3839

Fee (in PhP)

Initial Renewal

(2 years) (3 years)

1. Drug Manufacturer (Repacker, Packer)

<20M and below P20,000 P30,000

20-50M P30,000 P45,000

>50M P40,000 P60,000

2. Drug Trader

<20M and below P6,000 P9,000

20-50M P10,000 P15,000

>50M P14,000 P21,000

3. Drug Distributor (Exporter, Importer, Wholesaler) P10,000 P15,000

4. Drugstore/Pharmacy/Botica and similar outlets P2,000 P3,000

5. Retail Outlet for Non-Prescription Drugs (RONPD) P2,000 P3,000

6. Contract Research Organization/Sponsor P10,000 P15,000

PRODUCT REGISTRATION

Fee (in PhP)

Initial Renewal

(5 years) (5 years)

1. New P40,000

2. Generic Products40

Unbranded Products P10,000 P7,500

Branded Products P15,000 P10,000

3. Biotechnological Products



4. Other Drug Product Classification


36

Administrative Order No. 50 s. 2001, Revised 2001 Schedule of Fees and Charges for the Corresponding

Services Rendered by the Bureau of Food and Drugs 37

FDA Circular No. 2011-003, Collection of Legal Research Imposed by Republic Act No. 3870, as amended

by PD 200 and further amended by PD 1856 38

LTO fees are categorized according to the capital investment of the establishment 39

Fees for LTO differ in those provided under AO 50 as with the fees presented due to validity differences 40

Due to RA 6675, products identified by their generic name only and without trade names are given discounts

on the registration fee as their incentives

- 31 -


CLINICAL TRIAL, FOREIGN GMP,

CERTIFICATION AND OTHER FEES Fee (in PhP)

1. Clinical Trial Protocol P2,500/phase

2. Amendment of Protocol P1,000/phase

3. Import Permit P500

4. Compassionate Special Permit P500

5. Certificate of Pharmaceutical Product P500

6. Initial Foreign GMP Clearance P10,000 (per importer per site)

7. Renewal Foreign GMP Clearance P2,000

8. Application for Foreign GMP Inspection P3,000

9. Inspection Fees

ASEAN US$ 3,500 + UNDP-DSA

Asia Pacific US$ 7,000 + UNDP-DSA

Others US$ 10,000 + UNDP-DSA

Table 3. Fees and Charges for LTO, CPR, Clinical Trials, Foreign GMP, and Other

Certifications

In 2013, the FDA initiated the review of the existing fees and charges.

- 32 -

VI. References

Website

1. Republic of the Philippines, Food and Drug administration: http://www.fda.gov.ph/

2. Drug Establishment Licensing Requirements: http://www.fda.gov.ph/industry-

corner/downloadables/221-drug-establishment-licensing-requirements

3. Drug Registration Requirements: http://www.fda.gov.ph/industry-

corner/downloadables/217-requirements-for-drug-registration

4. Integrated Application Form and Process: http://www.fda.gov.ph/industry-

corner/downloadables/237-integrated-application-form-and-process

http://www.fda.gov.ph/

http://www.fda.gov.ph/industry-corner/downloadables/221-drug-establishment-licensing-requirements

http://www.fda.gov.ph/industry-corner/downloadables/221-drug-establishment-licensing-requirements



http://www.fda.gov.ph/industry-corner/downloadables/237-integrated-application-form-and-process

http://www.fda.gov.ph/industry-corner/downloadables/237-integrated-application-form-and-process

- 33 -

Appendix 1. Organization of ACTD

The registration dossier is organized into four parts as follows:


Sec. A Introduction

Sec. B Table of Contents

1. Application Form

2. Letter of Authorization (where applicable)

3. Certifications

4. Labeling

5. Product Information

Sec. C Guidance on the Administrative Data and Product Information

1. Application Form

2. Letter of Authorization (where applicable)

3. Certifications

For contract manufacturing:

a. License of pharmaceutical industries and contract manufacturer

b. Contract manufacturing agreement

c. GMP certificate of contract manufacturer

For manufacturing “under-license”

a. License of pharmaceutical industries

b. GMP certificate of the manufacturer

c. Copy of “under-license” agreement

For locally manufactured

a. License of pharmaceutical industries

b. GMP certificate (country specific)

For imported products

a. License of pharmaceutical industries/importer/wholesaler

(country specific)

b. Certificate of Pharmaceutical Product issued by the competent

authority in the country of origin according to the current WHO

format

c. Site Master File of the manufacturer (unless previously submitted

within the last 2 years) (country specific)

4. Labeling

5. Product Information

5.1. Package Insert

5.2. Summary of Product Characteristics (Product Data Sheet)

5.3. Patient Information Leaflet (PIL)

Part II: Quality

Sec. A Table of Contents

Sec. B Quality Overall Summary

- 34 -

Sec. C Body of Data

Drug Substance (S)

S 1 General Information

S 1.1. Nomenclature

S 1.2. Structural Formula

S 1.3. General Properties

S 2 Manufacture

S 2.1. Manufacturer(s)

S 2.2. Description of Manufacturing Process and Process Controls

S 2.3. Control of Materials

S 2.4. Control of Critical Steps and Intermediates

S 2.5. Process Validation and/or Evaluation

S 2.6. Manufacturing Process Development

S 3 Characterization

S 3.1. Elucidation of Structure and Characteristics

S 3.2. Impurities

S 4 Control of Drug Substance

S 4.1. Specifications

S 4.2. Analytical Procedures

S 4.3. Validation of Analytical Procedures

S 4.4. Batch Analyses

S 4.5. Justification of Specifications

S 5 Reference Standards or Materials

S 6 Container Closure System

S 7 Stability

Drug Product (P)

P 1 Description and Composition

P 2 Pharmaceutical Development

P 2.1. Information on Development Studies

P 2.2. Components of the Drug Product

P 2.2.1. Active Ingredients

P 2.2.2. Excipients

P 2.3. Finished Product

P 2.3.1. Formulation Development

P 2.3.2. Overages

P 2.3.3. Physicochemical and Biological Properties

P 2.4. Manufacturing Process Development

P 2.5. Container Closure System

P 2.6. Microbiological Attributes

P 2.7. Compatibility

P 3 Manufacture

P 3.1. Batch Formula

P 3.2. Manufacturing Process and Process Control

P 3.3. Controls of Critical Steps and Intermediates

- 35 -

P 3.4. Process Validation and/or Evaluation

P 4 Control of Excipients

P 4.1. Specifications

P 4.2. Analytical Procedures

P 4.3. Excipients of Human and Animal Origin

P 4.4. Novel Excipients

P 5 Control of Finished Product

P 5.1. Specifications

P 5.2. Analytical Procedures

P 5.3. Validation of Analytical Procedures

P 5.4. Batch Analyses

P 5.5. Characterization of Impurities

P 5.6. Justification of Specifications

P 6 Reference Standards or Materials

P 7 Container Closure System

P 8 Product Stability

P 9 Product Interchangeability

Part III: Nonclinical Document


Sec. B Nonclinical Overview

1. General Aspect

2. Content and Structural Format

Sec. C Nonclinical Written and Tabulated Summaries

1. Nonclinical Written Summaries

1.1. Introduction

1.2. General Presentation Issues

2. Content of Nonclinical Written and Tabulated Summaries

2.1. Pharmacology

2.1.1. Written Summary

2.1.1.1. Primary Pharmacodynamics

2.1.1.2. Secondary Pharmacodynamics

2.1.1.3. Safety Pharmacology

2.1.1.4. Pharmacodynamic Drug Interactions

2.1.2. Tabulated Summary

2.2. Pharmacokinetics


2.2.1.1. Absorption

2.2.1.2. Distribution

2.2.1.3. Metabolism

2.2.1.4. Excretion

2.2.1.5. Pharmacokinetic Drug Interaction

(Nonclinical)


- 36 -

2.3. Toxicology


2.3.1.1. Single-Dose Toxicity

2.3.1.2. Repeat-Dose Toxicity

2.3.1.3. Genotoxicity

2.3.1.4. Carcinogenicity

2.3.1.5. Reproductive and Developmental Toxicity

2.3.1.5.1. Fertility and Early Embryonic

Development

2.3.1.5.2. Embryo-Foetal Development

2.3.1.5.3. Prenatal and Postnatal

Development

2.3.1.6. Local Tolerance

2.3.1.7. Other Toxicity (if available)


3. Nonclinical Tabulated Summaries

Sec. D Nonclinical Study Reports

1. Table of Contents

2. Pharmacology

2.1. Written Study Reports

2.1.1. Primary Pharmacodynamics

2.1.2. Secondary Pharmacodynamics

2.1.3. Safety Pharmacology

2.1.4. Pharmacodynamic Drug Interactions

3. Pharmacokinetics


3.1.1. Analytical Methods and Validation Reports

3.1.2. Absorption

3.1.3. Distribution

3.1.4. Metabolism

3.1.5. Excretion

3.1.6. Pharmacokinetic Drug Interaction (Nonclinical)

3.1.7. Other Pharmacokinetic Studies

4. Toxicology


4.1.1. Single-Dose Toxicity

4.1.2. Repeat-Dose Toxicity

4.1.3. Genotoxicity

4.1.3.1. In-vitro Reports

4.1.3.2. In-vivo Reports

4.1.4. Carcinogenicity

4.1.4.1. Long Term Studies

4.1.4.2. Short or Medium Term Studies

4.1.4.3. Other Studies

4.1.5. Reproductive and Developmental Toxicity

- 37 -

4.1.5.1. Fertility and Early Embryonic Development

4.1.5.2. Embryo-Foetal Development

4.1.5.3. Prenatal and Postnatal Development

4.1.5.4. Studies in which the Offspring are Dosed

and/or further Evaluated

4.1.6. Local Tolerance

4.1.7. Other Toxicity Studies (if available)

4.1.7.1. Antigenicity

4.1.7.2. Immunotoxicity

4.1.7.3. Dependence

4.1.7.4. Metabolites

4.1.7.5. Impurities

4.1.7.6. Other

Sec. E List of Key Literature References

Part IV: Clinical Document


Sec. B Clinical Overview

1. Product Development Rationale

2. Overview of Biopharmaceutics

3. Overview of Clinical Pharmacology

4. Overview of Efficacy

5. Overview of Safety

6. Benefits and Risks Conclusions

Sec. C Clinical Summary

1. Summary of Biopharmaceutic Studies and Associated Analytical Method

1.1. Background and Overview

1.2. Summary of Results of Individual Studies

1.3. Comparison and Analyses of Results Across Studies

Appendix 1

2. Summary of Clinical Pharmacology Studies

2.1. Background and Overview



2.4. Special Studies

Appendix 2

3. Summary of Clinical Efficacy

3.1. Background and Overview of Clinical Efficacy



3.4. Analysis of Clinical Information Relevant to Dosing

Recommendations

3.5. Persistence of Efficacy and/or Tolerance Effects

Appendix 3

- 38 -

4. Summary of Clinical Safety

4.1. Exposure to the Drug

4.2. Adverse Events

4.3. Clinical Laboratory Evaluations

4.4. Vital Signs, Physical Finding, and Other Observations Related to

Safety

4.5. Safety in Special Groups and Situations

4.6. Post-Marketing Data

Appendix 4

5. Synopses of Individual Studies

Sec. D Tabular Listing of All Clinical Studies

Sec. E Clinical Study Reports (if applicable)

1. Reports of Biopharmaceutic Studies

1.1. BA Study Reports

1.2. Comparative BA or BE Study Reports

1.3. In vitro-In vivo Correlation Study Reports

1.4. Reports of Bioanalytical and Analytical Methods for Human

Studies

2. Reports of Studies Pertinent to Pharmacokinetics Using Human

Biomaterials

2.1. Plasma Protein Binding Study Reports

2.2. Reports of Hepatic Metabolism and Drug Interaction Studies

2.3. Reports of Studies Using Other Human Biomaterials

3. Reports of Human Pharmacokinetic (PK) Studies

3.1. Healthy Subject PK and Initial Tolerability

3.2. Patient PK and Initial Tolerability Study Reports

3.3. Population PK Study Reports

4. Reports of Human Pharmacodynamic (PD) Studies

4.1. Healthy Subject PD and PK/PD Study Reports

4.2. Patient PD and PK/PD Study Reports

5. Reports of Efficacy and Safety Studies

5.1. Study Reports of Controlled Clinical Studies Pertinent to the

Claimed Indication

5.2. Study Reports of Uncontrolled Clinical Studies

5.3. Reports of Analyses of Data from more than One Study, Including

any Formal Integrated Analyses, Meta-Analyses, and Bridging

Analyses

5.4. Other Clinical Study Reports

6. Reports of Post-Marketing Experience

7. Case Report Forms and Individual Patient Listing

Sec. F List of Key Literature References

- 39 -

Appendix 2. List of Molecules Requiring Proof of Interchangeablity

Classification of Selected Drugs belonging to the World Health Organization (WHO) Model

List of Essential Medicines (EML) Based on the Biopharmaceutics Classification System

I. Class 4 Drugs (low solubility, low permeability) based on the revised WHO criteria

for BCS

A. Substances on the WHO-EML

1) Acetazolamide

2) Albendazole (chewable tablet)

3) Artemether + Lumefantrine

4) Azithromycin

5) Cefixime

6) Clofazimine

7) Diloxanide furoate

8) Efavirenz

9) Erythromycin stearate and Erythrimycin ethylsuccinate

10) Furosemide

11) Glibenclamide

12) Haloperidol

13) Indinavir sulfate

14) Ivermectin

15) Lopinavir + Ritonavir

16) Mebendazole (chewable tablet)*

17) Mefloquine hydrochloride

18) Nelfinavir mesilate

19) Niclosamide (chewable tablet)*

20) Pyrantel embonate (chewable tablet)*

21) Pyrimethamine

22) Retinol palmitate

23) Ritonavir

24) Saquinavir

25) Spironolactone

26) Sulfasalazine**

27) Triclabendazole

B. Substances on the Complementary List of the WHO-EML

1) Artesunate

2) Azathioprine sodium

3) Ciclosporin

4) Etoposide

5) Mercaptopurine

6) Mifepristone

7) Oxamniquine

- 40 -

8) p-Aminosalicylic Acid

9) Sulfadiazine

10) Pyrimethamine in Sulfadoxine + Pyrimethamine

II. Class 3 Drugs (low permeability, high solubility) based on the revised WHO criteria

for BCS


1) Abacavir

2) Aciclovir

3) Amodiaquine

4) Atenlol

5) Clavulanic acid in Amoxicillin + Clavulanic Acid

6) Benznidazole

7) Biperiden hydrochloride

8) Chloramphenicol

9) Chlorphenamine hydrogen maleate

10) Chlorpromazine hydrochloride

11) Ciprofloxacin hydrochloride

12) Clomifene citrate

13) Clomipramine hydrochloride

14) Cloxacillin sodium

15) Codeine phosphate

16) Didanosine (Buffered chewable tablet, dispersible tablet)

17) Enalapril

18) Ergocalciferol

19) Ethambutol hydrochloride

20) Ethinylestradiol

21) Ethinylestradiol in Ethinylestradiol + Levonorgestrel

22) Ethinylestradiol in Ethinylestradiol + Norethisterone

23) Ferrous sulfate

24) Ferrous salt + Folic acid

25) Folic Acid

26) Glyceryl trinitrate (sublingual application)

27) Hydralazine hydrochloride

28) Hydrochlorothiazide

29) Isoniazid

30) Isoniazid + Ethambutol

31) Isosorbide dinitrate (sublingual application)*

32) Levamisole hydrochloride

33) Carbidopa in Levodopa + Carbidopa

34) Levothyroxine sodium

35) Metformin hydrochloride

36) Methyldopa

37) Metoclopramide hydrochloride

- 41 -

38) Morphine sulfate

39) Neostigmine bromide

40) Nifurtimox

41) Penicillamine

42) Pyrazinamide

43) Ranitidine hydrochloride

44) Isoniazid in Rifampicin + Isoniazid

45) Isoniazid in Rifampicin + Isoniazid + Pyrazinamide

46) Isoniazid in Rifampicin + Isoniazid + Pyrazinamide + Ethambutol

47) Ethambutol in Rifampicin + Isoniazid + Pyrazinamide + Ethambutol

48) Thiamine hydrochloride

49) Zinc sulfate


1) Chlorambucil

2) Cycloserine

3) Ethionamide

4) Ethosuximide

5) Flucytosine

6) Levamisole hydrochloride

7) Methotrexate sodium

8) Pentamine

9) Procarbazine hydrochloride

10) Pyridostigmine bromide

11) Quinidine sulfate

12) Sulfadoxine in Sulfadoxine Pyrimethamine

III. Class 2 Drugs (high permeability, low solubility) not eligible for biowaiver based on



1) Carbamazepine

2) Dapsone

3) Griseofulvin

4) Iopanoic acid

5) Nevirapine

6) Nitrofurantoin

7) Praziquantel

8) Sulfamethoxzole + Trimethoprim

9) Trimethoprim

10) Verapamil hydrochloride

IV. Class 2 Drugs (high permeability, low solubility) with weak acidic properties based

on the revised WHO criteria for BCS

- 42 -


1) Ibuprofen

2) Phenytoin sodium

V. Class 1 Drugs (high permeability, high solubility) based on the revised WHO criteria

for BCS


1) Acetylsalicylic acid

2) Allopurinol

3) Amiloride hydrochloride

4) Amitriptyline hydrochloride

5) Amlodipine

6) Amoxicillin

7) Ascorbic acid

8) Chloroquine phosphate and Chloroquine sulfate

9) Diazepam

10) Digoxin

11) Doxycycline hydrochloride

12) Fluconazole

13) Lamivudine

14) Levonorgestrel

15) Lithium carbonate

16) DL-Methionine

17) Metronidazole

18) Nicotinamide

19) Noethisterone

20) Paracetamol

21) Phenobarbital

22) Phenoxymethyl penicillin potassium

23) Potassium iodide

24) Prednisolone

25) Primaquine diphosphate

26) Proguanil hydrochloride

27) Promethazine hydrochloride

28) Propranolol hydrochloride

29) Propylthiouracil

30) Pyridoxine hydrochloride

31) Quinine bisulfate and Quinine sulfate

32) Riboflavin

33) Salbutamol sulfate

34) Stavudine

35) Valproic acid sodium

36) Warfarin sodium

37) Zidovudine

- 43 -


1) Calcium folinate

2) Clindamycin

3) Cyclophosphamide

4) Diethylcarbamazine dihydrogen citrate

5) Levofloxacin

6) Ofloxacin

7) Prednisolone

8) Tamoxifen citrate

- 44 -

Appendix 3. Details on the Minimum Labeling Information

1) Product Name

(a) The product name shall indicate the generic name and the brand name (if any) of the

drug product.

(b) The generic name shall be as the active moiety based on the International Non-

proprietary Name (INN), and consistent with the dosage strength indicated; for

prodrugs, the generic name shall be the INN of the prodrug itself and not its active

chemical (metabolite) form.

(c) The generic name shall appear prominently with an outline box, with the generic

name’s prominence over the other information being clearly and distinctly readable

by normal vision as may be determined by common visual sense.

(d) For herbal medicines and traditionally-used herbal products, the generic name shall

be the botanical origin or as recognized by the FDA.

(e) If a product is identified by a brand name together with its generic name, the generic

name enclosed in an outline box shall in all cases appear immediately above the

brand name; for narrative texts (whether in the unit carton, primary label or insert),

the brand name shall in all cases be preceded by the generic name and enclosed in

parentheses or brackets.

(f) For products with multiple APIs, the product name shall indicate all of the APIs,

enumerated in the order of decreasing pharmacologic activity and placed inside the

box in either of the given format:

E.g.:

Iron

Folic Acid

Brand Name

Iron / Folic Acid

Brand Name

Iron + Folic Acid

Brand Name

If the APIs have more or less similar pharmacologic activity, they shall be

enumerated in the order of decreasing potency and strength; provided, that if there

exists a single approved name for fixed-dose combination (e.g. Cotrimoxazole for

the standard formulation Sulfamethoxazole / Trimethoprim), the single approved

name shall be used; provided further, that if there is no single approved name but

there exist a generic class name (e.g. Multivitamins for multi-vitamin containing

preparations, as approved by the FDA), the generic class name shall be used.

The individual components of the single approved name and generic class name

shall be enumerated under Formulation.

- 45 -


(a) The label shall specify the (i) dosage form of the product such as tablet, capsule,

suspension, ointment, etc., (ii) the specific delivery system, if any, such as modified

release, and (iii) specific mode of administration, if any, and appropriate, such as

vaginal/rectal suppository, etc., as approved by the FDA. If there is no qualifier for

tablets, it is understood as an oral, uncoated, immediate release tablet.

(b) The label shall specify the dosage strength of the product which shall be expressed

in metric units reduced to lowest terms and in the number of the largest unit

specified (e.g. 500 mcg, not 0.5 mg).

(c) The FDA, as deemed necessary and appropriate, shall allow the strength of certain

dosage forms (e.g. semisolid, ophthalmic, otic, nasal, and topical preparations) to be

expressed as percentage.

(d) For products with multiple APIs, the dosage strength shall be stated in accordance

with the generic name indicated: for multiple APIs, the individual strengths shall be

indicated, separated by a slash sign (/); if a single approved name is used, the dosage

strength shall be indicated as the sum.

E.g.:

Piperacillin / Tazobactam

Brand Name

4 g / 500 mg Powder for Injection (IV)

Piperacillin + Tazobactam

Brand Name


Piperacillin

Tazobactam

Brand Name


Cotrimoxazole

Brand Name

960 mg Tablet


The pharmacologic category shall be as determined by the FDA, taking into

consideration current acceptable standards for therapeutic categories.


(a) The label shall state the name and strength of all APIs present per unit dose of the

product, which shall be arranged in decreasing pharmacologic activity, or if having

more or less similar pharmacologic activity, in decreasing potency and strength.

(b) The generic name of the API shall be stated in full (including salts and esters, if any)

and correlated to the active moiety, when applicable. The name of the API shall be

in accordance with its INN; for herbal medicines and traditionally-used herbal

- 46 -

products, the official Philippine Pharmacopoeia name shall be used, or as

determined by the FDA.

(c) The reference monograph recognized by the FDA (e.g. USP, BP, EP, JP, PP, Ph. Int)

used for the analysis of the finished drug product shall be indicated immediately

after the API, unless a non-official method is used; for multiple APIs, it shall be

indicated after the first API.

E.g.:

(d) Alcohol, when present in the product shall also be indicated, expressed as a

percentage (%). The name “alcohol” without qualification shall mean ethyl alcohol.

(e) The coloring, antimicrobial, and antioxidant agents, and preservatives used in the

manufacture of the product that may cause hypersensitivity and/or other adverse

drug reactions shall also be indicated, with the amount expressed in the same manner

as the API.

5) Indication(s)

The indication(s) stated in the labeling materials shall include only the FDA-approved

clinical use(s) of the drug product.

6) Dosage and Mode of Administration

(a) The label shall contain full information on the product’s recommended dosage,

including the (i) initial or loading dose, (ii) optimal use or usual dose, (iii) frequency

interval, (iv) duration of treatment, (v) dosage adjustment, and other pertinent

aspects of drug therapy, if applicable.

(b) Relevant information regarding dilution (e.g. the specific volume of diluent to be

added), reconstitution, preparation, and administration shall also be included (such

Each tablet contains:

Sodium Ascorbate, USP....................................562.5 mg

(equivalent to Ascorbic Acid 500 mg) (Vitamin C)


Sulfamethoxazole, USP.........................................800mg

Trimethoprim.........................................................160mg

Each vial contains:

Omeprazole (as Sodium) ........................................40mg


Calcium Carbonate, BP.........................................750mg

(equivalent to elemental Calcium 300 mg)

Each capsule contains:

Amoxicillin (as Trihydrate), USP..........................500mg

- 47 -

as “Shake well before use” for suspensions, “Do not crush” for tablets with special

delivery system, etc.) in all labeling materials. The label shall include a description

of the reconstituted preparation.

(c) Separate directions for use by special populations, adults, and children shall be

stated. If the product is not recommended for children, the dosage shall be clearly

identified as “Adult dose”, or any statement to that effect.

7) Contraindication(s), Precaution(s), Warning(s)

(a) The label shall contain full information regarding the contraindication(s) of the drug

product, as well as the precaution(s) to be observed in its administration and use.

(b) The label shall include warning statements, as required and/or specified by the FDA

(e.g. “Flammable,” “For external use only,” “Keep out of reach of children”). Other

specific additional instructions shall be issued by the FDA in appropriate regulations.

(c) Where the contents of a container are to be used on one occasion only, the label shall

include the statement, “Single use only”, “Single dose”, “Use only once”, “Discard

any remaining portion”, or any statement to that effect.

8) Interactions

The label shall include drug-drug, drug-food, drug-laboratory testing interactions, as well

as other relevant interactions, if applicable.


The label shall include detailed information on adverse drug reaction(s) for a drug

product arranged by system organ class.


The label shall include signs and symptoms of overdose, as well as possible treatment.


(a) The label shall indicate appropriate storage condition(s) and special instructions for

handling of the drug product.

(b) Special labeling instructions shall be added for drug products with the following

properties:

Properties Special labeling instructions

Cannot tolerate refrigeration “Do not refrigerate or freeze”

Cannot tolerate freezing “Do not freeze”

Light-sensitive “Protect from light”

Cannot tolerate excessive heat,

e.g. suppositories

“Store and transport not above

30 °C”

Hygroscopic “Store in dry conditions”

12) Pack Size or Net Content

(a) The unit carton shall indicate the pack size of the drug product expressed in terms

of the number of units in the pack or the volume of each unit, e.g. 60 mL (for

- 48 -

liquids), 10 blister packs x 10 tablets (for tablets), 100 tablets, 12 sachets x 5 g, etc.;

Provided, that in case of drug products for reconstitution for oral administration, the

pack size shall reflect the volume of the product as reconstituted.

(b) For the primary label excluding blisters and foil strips, the net content of the

product, stating the total amount/quantity/number of the dosage form in a given

container shall be expressed in metric units, e.g. 60 mL (for liquids), 5 g (for sachets)

13) Name and Address of Marketing Authorization Holder

The label shall state the name and full address of the MAH of the drug product.


The label shall state the name of the manufacturer and full address of the specific

manufacturing site of the drug product as determined by the FDA.

15) Rx Symbol and Caution Statement

(a) The labeling materials of prescription drug products shall always include the Rx

symbol, which shall be prominently displayed. The Rx symbol may be allowed to be

over-printed or superimposed, provided, that such will not result in the obliteration

by or being rendered less legible than other required labeling information.

(b) The caution statement, “Foods, Drugs, Devices, and Cosmetics Act prohibits

dispensing without prescription.” shall always be included in the package insert,

unit carton, primary label except blister pack, foil strip, and small containers of

prescription drug products. In addition, for products classified as Dangerous Drug as

per Republic Act No. 9165, the caution statement shall be followed by an additional

statement as specified by the Philippine Drug Enforcement Agency (PDEA).


For the product information sheet and the unit carton or primary label except

blister pack, foil strip, and small containers of products intended to be sold without

a unit carton, the statement “For suspected adverse drug reaction, report to the FDA:

www.fda.gov.ph” shall appear. In addition, a statement instructing the patient to seek

medical attention immediately at the first sign of any adverse drug reaction shall appear.

The MAH may also include a reporting statement for their own pharmacovigilance

system.


The label shall indicate the registration number assigned by the FDA to the product,

which is denoted by a combination of letters and/or numbers.

18) Batch Number and Lot Number

The label shall indicate the product’s batch number; provided, that if the entire batch is

marketed by one drug establishment, only the batch number shall be indicated. However,

if a batch is divided into lots marketed by different drug establishments, the lot number

and corresponding batch number shall be indicated.

- 49 -


(a) The label shall bear the month and year of the product’s manufacturing and

expiration date either in letters or words and numbers, or in numbers alone; if

expressed in numbers alone, the year shall be stated completely in order to

distinguish it from the month; and if the day is specified, the month shall be spelled

out, as shown below:

June 2007 or Jun 2007

06/2007

03 June 2007 or 03 Jun 2007

(b) Unless a certain day of the month is specified, the last day of the stated month shall

be deemed as the date of the product’s expiration/manufacturing date.

(c) For products reconstituted prior to use and those which can be administered multiple

times (e.g. suspensions), the label shall include the period of guaranteed safety,

efficacy, and quality of the reconstituted preparation/after first opening at a given

storage condition(s).

- 50 -

Appendix 4. List of Information Required per Labeling Material

A. Unit Carton

The unit carton shall contain the following minimum information:

1) Product Name




5) Indication(s)

6) Warning(s) (if applicable)

7) Storage condition(s)

8) Pack Size



11) For prescription drug products, the Rx Symbol and Caution Statement





B. Primary Label excluding blister pack, foil strip and small containers

The primary label shall contain the following minimum information:

1) Product Name




5) Indication(s)

6) Warning(s) (if applicable)

7) Storage condition(s)

8) Net Content



11) For prescription drug products, the Rx Symbol and Caution Statement

12) ADR Reporting Statement (if without accompanying unit carton)




C. Blister Packs/Foil Strips

The standard blister pack/foil strip packaging of a drug product shall contain the

following minimum information:

1) Product name on each unit for single API, or every two (2) units for multiple

APIs

- 51 -

2) Dosage form and strength of API on each unit for single API, or every two (2)

units for multiple APIs

3) Name and/or logo of the Marketing Authorization Holder on each unit for single

API, or every two (2) units for multiple APIs (for unbranded products only)

4) Rx symbol on each unit for single API, or every two (2) units for multiple APIs.

5) Batch number and expiration date on every standard blister pack/foil strip, provided

that, when the pharmaceutical product is not restricted to be dispensed in quantities

less than the standard blister pack or foil strip, the batch or lot number and expiration

date shall be indicated on each unit

D. Primary label of small containers

The primary label of small containers shall contain the following minimum information:

1) Product name


3) Net Content

4) Name and/or Logo of Marketing Authorization Holder

5) Rx Symbol (if applicable)



8) Batch and/or Lot Number (if any)


Due consideration may be given in view of limited space on the label.

E. Package Insert

The package insert shall contain the following minimum information:

1) Product Name



4) Product Description


6) Pharmacodynamics and Pharmacokinetics

7) Indication(s)

8) Dosage and Mode/Route of Administration

9) Contraindication(s), Precaution(s), Warning(s) (if applicable)

10) Pregnancy and Lactation (if applicable)

11) Interactions




15) Dosage Forms and Packaging Available (pack size)

16) Instructions and Special Precautions for Handling and Disposal (if applicable)



19) Caution Statement

- 52 -



22) Date of First Authorization/Renewal of the Authorization

23) Date of Revision of Package Insert

Products with varying strengths may opt to use a common insert, provided that individual

product description, packaging, formulation, or other differing information between the

strengths are included.

F. Patient Information Leaflet

PIL shall be prepared and written in layman’s terms, and shall contain the following

minimum information:

1) Name of the Product

2) Description of the Product

3) What is in the Medicine?

4) Strength of the Medicine

5) What is this Medicine used for?

6) How much and how often should you use this Medicine?

7) When should you not take this Medicine?

8) Care that should be taken when taking this Medicine?

9) Undesirable Effects of this Medicine

10) What other medicine or food should be avoided while taking this Medicine?

11) What should you do if you miss a dose?

12) Signs and Symptoms of Overdose

13) What to do when you have taken more than the recommended dosage?

14) How should you keep this Medicine?

15) When should you consult your doctor?





20) Date of First Authorization/Renewal of the Authorization

21) Date of Revision of Patient Information Leaflet

- 53 -

Appendix 5. List of Post Approval Changes

A. ASEAN Variation Guidelines

MAJOR VARIATION (MaV) MaV-1 Change and/or additional indication/dosing regimen/patient

population/inclusion of clinical information extending the usage of the

product

MaV-2 Change of content of product labeling MaV-3 Change and/or addition of alternative manufacturer/site of drug substance

[where European Pharmacopoeial Certificate of Suitability (CEP) is not

available]

MaV-4 Addition or replacement of the manufacturing site of the drug product

MaV-5 Addition or replacement of the alternative site for the primary packaging

(direct contact with drug product)

MaV-6 Change of the specification drug substance and/or drug product [where

European Pharmacopoeial Certificate of Suitability (CEP) is not available]

MaV-7 Change of batch size of sterile drug product

MaV-8 Change of batch size of non-sterile drug product

MaV-9 Major change in the manufacturing process for the drug product

MaV-10 Qualitative or quantitative change of excipient

MaV-11 Quantitative change in the coating weight of tablets or weight and/or size of

capsule shell for modified release oral dosage form

MaV-12 Change in primary packaging material for sterile product a) Qualitative and

quantitative composition and/or

b) Type of container and/or

c) Inclusion of primary packaging material

MaV-13 Change or addition of pack size/fill volume and/or change of shape or

dimension of container or closure for a sterile solid and liquid drug product

MaV-14 Inclusion or replacement of the solvent/diluent for the drug product

MaV-15 Extension of shelf-life of the drug product

MaV-16 Change of storage conditions of the drug product (Lowering from the

current approved storage condition)

MINOR VARIATION PRIOR APPROVAL (MiV-PA)

MiV-PA1 Change of drug product name

MiV-PA2 Change of product labeling (in accordance to country specific labeling

requirement)

MiV-PA3 Addition or replacement of the company or party responsible for batch

release

MiV-PA4 Change and/or addition of alternative manufacturer/site of drug substance

[where European Pharmacopoeial Certificate of Suitability (CEP) is

available]

MiV-PA5 Change of batch size of drug substance [where European

Pharmacopoeial Certificate of Suitability (CEP) is not available]

- 54 -

MiV-PA6 Change of in-process controls applied during the manufacture of the drug

substance [including tightening and addition of new in- process test and

where European Pharmacopoeial Certificate of Suitability (CEP) is not

available]

MiV-PA7 Change of manufacturing process of the drug substance [where European

Pharmacopoeial Certificate of Suitability (CEP) is not available]

MiV-PA8 Change of the specification of drug substance

MiV-PA9 Change of the test procedure of non-compendial drug substance

MiV-PA10 Change of shelf-life or retest period for drug substance

MiV-PA11 Change of storage condition for drug substance

MiV-PA12 Revision of European Pharmacopoeial Certificate of Suitability

(CEP) of drug substance

MiV-PA13 Change of batch size of non-sterile drug product

MiV-PA14 Reduction or removal of overage

MiV-PA15 Qualitative or quantitative change of excipient

MiV-PA16 Quantitative change in coating weight of tablets or weight and/or size of

capsule shell for immediate release oral dosage form

MiV-PA17 Change of the colouring/flavouring agent of the product [addition, deletion

or replacement of colourant(s)/flavour(s)]

MiV-PA18 Deletion of the solvent/diluent for the drug product

MiV-PA19 Change of in-process controls applied during the manufacture of the drug

product (including tightening and addition of new in- process test)

MiV-PA20 Minor change of the manufacturing process for non-sterile product.

MiV-PA21 Change of specifications of an excipient

MiV-PA22 Change of a test procedure for an excipient, including replacement of an

approved test procedure by a new test procedure

MiV-PA23 Change in the source of empty hard capsule

MiV-PA24 Change of release and shelf-life specifications of the drug product

MiV-PA25 Change of imprints, bossing or other markings on the tablets or printing on

capsules including addition or change of inks used for product marking

MiV-PA26 Change of dimensions and/or shape of tablets, capsules, suppositories or

pessaries without change in qualitative and quantitative composition and

mean mass

MiV-PA27 Change in the test procedure of the drug product (including replacement or

addition of a test procedure)

MiV-PA28 Change in primary packaging material for non-sterile product a) Qualitative

and quantitative composition and/or

b) Type of container and/or

c) Inclusion of primary packaging material

MiV-PA29 Addition or replacement of a manufacturer for secondary

packaging

MiV-PA30 Change of pack size/fill volume and/or change of shape or dimension of

container or closure for non-sterile product

- 55 -

MiV-PA31 Change of outer carton pack sizes for a drug product

MiV-PA32 Change in any part of the (primary) packaging material not in contact with

the finished product formulation (such as colour of flip- off caps, colour

code rings on ampoules, change of needle shield (different plastic used)

MiV-PA33 Addition or replacement of measuring device for oral liquid dosage forms

and other dosage form

MiV-PA34 Reduction of shelf-life of the drug product

MiV-PA35 Change of storage conditions of the drug product (Increasing from the

current approved storage condition)

MINOR VARIATION NOTIFICATION (MiV-N) MiV-N1 Change in name and/or address of the marketing authorization holder

MiV-N2 Change of product owner

MiV-N3 Change in ownership of manufacturer

MiV-N4 Change of the name or address (for example: postal code, street name) of

the manufacturer of drug product

MiV-N5 Change of the name or address (for example: postal code, street name) of

the company or manufacturer responsible for batch release

MiV-N6 Change of the name and/or address (for example: postal code, street name)

of a manufacturer of the drug substance

MiV-N7 Withdrawal/deletion of the alternative manufacturer(s) (for drug

substance and/or drug product and/or packager)

MiV-N8 Renewal of European Pharmacopoeial Certificate of Suitability

(CEP)

MiV-N9 Change of release and shelf-life specifications of the drug product and/or

drug substance and/or excipient, following the updates in the compendium

MiV-N10 Deletion of pack size for a product

B. Country Specific Post-approval Changes

MAJOR VARIATION (MaV)

MV-PH1 Additional route of administration

MV-PH2 Change of manufacturing site (same subsidiary) of the drug product

MINOR VARIATION PRIOR APPROVAL (MiV-PA)

MV-PH3 Change of capsule color

MV-PH4 Change of brand name

MV-PH5 Change of MAH

MV-PH6 Reclassification (ex. Over-the-counter [OTC] to Prescription, OTC to

household remedy [HR])