Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
the Philippines
Drafted Version
(Expected to be revised)
May 2016
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.
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
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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
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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).
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)
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1.2 Tasks
The tasks of the abovementioned offices are as follows:
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
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;
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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
Website: www.fda.gov.ph
Email: info@fda.gov.ph, report@fda.gov.ph
Phone: +63 2 857 1900
Social Media: www.facebook.com/FDAPhilippines
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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:.
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
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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).
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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.
2. Generic drugs8
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”
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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 synonymous 12 . 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
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
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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)
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
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.
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
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2. Drug Application and Registration
2.1 Overview
Submission
Evaluation
No With Yes
deficiencies?
Releasing
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
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PAIR, by appointment schedule 19 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.
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”
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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 Part I Module 1
and Product Information
Common Technical Incorporated in Parts II, III, Module 2
Document Overview and and IV
Summaries
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
As new drugs are covered by ACTD, the required documents23 are as follows:
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
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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
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
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4. Generic drug approval application
The requirements for generic drug registration depend on the dispensing category of the
products. For prescription products, application dossier is based on ACTD:
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
Country specific requirement for both include submission of foreign GMP Clearance for
imported products.
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
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6. Facilitated Applications26
26
CDRR Memorandum No.: 0003, Series 2013, Facilitation of Applications for Product Registration
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V. Others
1.2.1 Documentation
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”
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GMP Evidence
GMP Evidence Dossier (required for Non-PIC/S countries)
Affidavit of Undertaking
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:
Manufacturing Steps
Documents Required Full Bulk
QC Testing
Packaging / Release for
Sterilization
Manufacture Manufacture Labeling supply
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
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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
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”
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2.1 Products Covered
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
the revised WHO criteria for BCS
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.
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
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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
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
- 27 -
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
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.
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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:
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.
35
FDA Circular No. 2014-008, Application Process and Requirements for Post-approval Changes of
Pharmaceutical Products
- 29 -
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.
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
- 30 -
Branded Products P15,000 P10,000
In 2013, the FDA initiated the review of the existing fees and charges.
- 31 -
VI. References
Website
1. Republic of the Philippines, Food and Drug administration: http://www.fda.gov.ph/
- 32 -
Appendix 1. Organization of ACTD
The registration dossier is organized into four parts as follows:
- 33 -
Sec. C Body of Data
Drug Substance (S)
S1 General Information
S 1.1. Nomenclature
S 1.2. Structural Formula
S 1.3. General Properties
S2 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
S3 Characterization
S 3.1. Elucidation of Structure and Characteristics
S 3.2. Impurities
S4 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
S5 Reference Standards or Materials
S6 Container Closure System
S7 Stability
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2.3. Toxicology
2.3.1. Written Summary
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)
2.3.2. Tabulated Summary
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. Written Study Reports
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. Written Study Reports
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
- 36 -
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
- 37 -
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
- 38 -
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
II. Class 3 Drugs (low permeability, high solubility) based on the revised WHO criteria
for BCS
III. Class 2 Drugs (high permeability, low solubility) not eligible for biowaiver based on
the revised WHO criteria for BCS
IV. Class 2 Drugs (high permeability, low solubility) with weak acidic properties based
on the revised WHO criteria for BCS
- 41 -
A. Substances on the WHO-EML
1) Ibuprofen
2) Phenytoin sodium
V. Class 1 Drugs (high permeability, high solubility) based on the revised WHO criteria
for BCS
- 43 -
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
- 44 -
2) Dosage Form and Strength
(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
4 g / 500 mg Powder for Injection (IV)
Piperacillin
Tazobactam
Brand Name
4 g / 500 mg Powder for Injection (IV)
Cotrimoxazole
Brand Name
960 mg Tablet
3) Pharmacologic Category
The pharmacologic category shall be as determined by the FDA, taking into
consideration current acceptable standards for therapeutic categories.
4) Formulation/Composition
(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
- 45 -
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.:
Each tablet contains:
Sodium Ascorbate, USP....................................562.5 mg
(equivalent to Ascorbic Acid 500 mg) (Vitamin C)
(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.
8) Interactions
The label shall include drug-drug, drug-food, drug-laboratory testing interactions, as well
as other relevant interactions, if applicable.
- 47 -
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)
- 48 -
19) Expiration Date and Date of Manufacture
(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).
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Appendix 4. List of Information Required per Labeling Material
A. Unit Carton
The unit carton shall contain the following minimum information:
1) Product Name
2) Dosage Form and Strength
3) Pharmacologic Category
4) Formulation/Composition
5) Indication(s)
6) Warning(s) (if applicable)
7) Storage condition(s)
8) Pack Size
9) Name and Address of Marketing Authorization Holder
10) Name and Address of Manufacturer
11) For prescription drug products, the Rx Symbol and Caution Statement
12) ADR Reporting Statement
13) Registration Number
14) Batch Number and Lot Number (if any)
15) Expiration Date and Date of Manufacture
B. Primary Label excluding blister pack, foil strip and small containers
The primary label shall contain the following minimum information:
1) Product Name
2) Dosage Form and Strength
3) Pharmacologic Category
4) Formulation/Composition
5) Indication(s)
6) Warning(s) (if applicable)
7) Storage condition(s)
8) Net Content
9) Name and Address of Marketing Authorization Holder
10) Name and Address of Manufacturer
11) For prescription drug products, the Rx Symbol and Caution Statement
12) ADR Reporting Statement (if without accompanying unit carton)
13) Registration Number
14) Batch Number and Lot Number (if any)
15) Expiration Date and Date of Manufacture
- 50 -
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
E. Package Insert
The package insert shall contain the following minimum information:
1) Product Name
2) Dosage Form and Strength
3) Pharmacologic Category
4) Product Description
5) Formulation/Composition
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
12) Adverse Drug Reaction(s)
13) Overdose and Treatment
14) Storage Condition(s)
15) Dosage Forms and Packaging Available (pack size)
16) Instructions and Special Precautions for Handling and Disposal (if applicable)
17) Name and Address of Marketing Authorization Holder
18) Name and Address of Manufacturer
19) Caution Statement
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20) ADR Reporting Statement
21) Registration Number
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.
- 52 -
Appendix 5. List of Post Approval Changes
A. ASEAN Variation Guidelines
- 53 -
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
- 54 -
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
- 55 -