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December 2014regulatoryfocus.org 1
By Ravi Varahalu and Jairam Masetti
This two-part series on the Southeast Asian regulatory environment for pharmaceuticals describes the regulatory landscape in each of the 10 Association of Southeast Asian Nations (ASEAN) countries and attempts to capture some of the key elements that compa-nies should consider when planning to enter ASEAN markets. Part 1 presents information on the larger ASEAN markets of Singapore, Malaysia, Thailand, Indonesia and Singapore. Part 2 will discuss Brunei, Vietnam, Laos, Myanmar (Burma) and Cambodia.
Currently, the ASEAN region covers an area of 4.5 million square kilometers and has a population of 618 million (approximately 8.9% of the world’s population).
The combined gross domestic product (GDP) has grown to $2.158 trillion (USD), but with significant disparities prevailing across the countries in the region. The pharmaceuti-cal market, although relatively small, still attracts many companies due to its high growth potential (see Table 1).
ASEAN Background
ASEAN’s main purpose is to accelerate economic growth, social progress and cultural development in the region. For several years, the Consultative Committee for Standards & Quality worked toward harmonization of pharmaceutical regulations, and an agreement was reached in July 2009. The harmonization process created transparent regulatory proce-dures, standardized regulation requirements and removed the need for duplicative studies.
Since 2010, drug companies have dealt with one set of regulatory requirements for all ASEAN countries as long as their dossiers are compliant with the ASEAN Common Technical Dossier (ACTD); however, in recent years, ASEAN health authorities have been organized differently and some significant regulatory changes have taken place, which are most evident in Singapore, Malaysia, Thailand and Indonesia (see Table 2).
The Southeast Asian Regulatory Environment for Pharmaceuticals (Part 1)
December 2014regulatoryfocus.org 2
Table 1. Southeast Asia Pharmaceutical Markets1
Countries Singapore Malaysia Thailand Philippines Indonesia
Population (millions)
5,469,700 30,331,000 64,871,000 100,617,630 252,164,800
Average GDP growth (%) (2011–15)
5.5(Q1/2014)
6.20(Q1/2014)
5.2(Q1/2014)
6.40(Q1/2014)
6.6(Q1/2014)
Pharma market growth (2013–14)
$790 million USD in 2013 to $840 million in 2014
$2.11 billion USD in 2013 to $2.28 billion in 2014
$4.6 billion USD in 2013 to $4.62 billion in 2014
$3.20 billion USD in 2013 to $4.5 billion in 2014
$6.05 billion USD in 2013 and 2014
Pharmaceutical industry growth rate (CAGR)
5.5% 7.30% 8.44% 4.99% 12.5%
Table 2. Regulatory Agencies, Approval Times and Fees
CountriesHealth Authority
Marketing Authorization Application (MAA) Approval Timelines Fees
Singapore Health Sciences Authority (HSA)
NDA:• Full NDA : 270 working days• Abridged NDA : 180• working days• Verification NDA: 60 working
daysGDA:• Abridged GDA: 240 working
days• Verification: 120 working days
Abridged: • NDA1 &NDA 2: approximately $8,800
USD• NDA 3: approximately $4,400 USD • GDA 1: approximately $3,080 USD• GDA 2: approximately $1,760 USDVerification:• NDA full dossier: approximately
$65,985 USD• NDA1 &NDA2: approximately $13,200
USD• NDA 3: approximately $4,400 USD • GDA 1: approximately $7,990 USD• GDA 2: approximately $4,000 USD
Malaysia National Pharmaceutical Control Bureau (NPCB)
NDA:• Full evaluation: 245 working
daysGeneric• Full evaluation 210 working
days• Abridged evaluation:
o Single active ingredient: 116 working days
o Two or more active ingredients: 136 working days
New drug:• Single active ingredient: approximately
$1,220 USD• Two or more active ingredients:• Approximately $1,530 USD
Generic: • Single active ingredient: approximately
$670 USD• Two or more active ingredients:
approximately $920 USD
Thailand ThaiFDA, Drug Control Division (TFDA)
New drug:• Standard: 210–280 working
days• Accelerated: 100–130
working days
New generic drug:• Standard: 110 working days• Accelerated: 70 working days
Fees:• To import drug: approximately $250
USD• To register a drug: approximately $65
USD• For a license to produce a drug:
approximately $200 USD
Philippines The Bureau of Food & Drugs (BFAD), Department of Health
• six to nine months • $465 USD per brand name drug• $220 USD per generic drug
Indonesia National Agency of Drug & Food Control (NADFC)
• New drug: 300 working days• Generic: 100–150 working
days
• Approximately $2,000 USD
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The ACTD is similar to the International Conference on Harmonisation (ICH) CTD with some notable differences (see Tables 3 and 4).
Table 4. Major Differences between ACTD and ICH CTD
ACTD (Part II) ICH CTD (Module 3)
S 7 Stability—no subsections 3.2.S.7 Stability—three subsections
P 2 Pharmaceutical Development—seven subsections
• P 2.1 information on development studies (additional)
3.2.P.2 Pharmaceutical Development—six subsections
P 3 Manufacture—four subsections 3.2.P.3 Manufacture—five subsections• 3.2.P.3.1 Manufacturer (s) (additional)
P 4 Control of Excipients—four subsections 3.2.P.4 Control of Excipients—six subsections• 3.2.P.4.3 Validation of analytical procedures
(additional)• 3.2.P.4.4 Justification of specification (additional)
P 8 Stability—no subsections 3.2.P.8 Stability—three subsections
P 9 Product Interchangeability Equivalence Evidence Not part of Module 3; covered separately in Module 5
Additional data submission requirements vary by country (see Table 5).
Table 5. Additional Document Requirements
Country Samples
Certificate of Pharmaceutical Products (CoPP)
Manufacturing License
Good Manufacturing
Practices (GMP) Certificate
Singapore NR R R PIC
Malaysia NR R R PIC
Thailand R R R R
Philippines R R R R
Indonesia NR R R PIC
R: Required NR: Not Required PIC: Pharmaceutical Inspection Convention
Singapore
In Singapore, under The Medicines Act, Section 5, a product license is required before a medicinal product can be sold or supplied unless otherwise exempted under the law. Each product license is specific to a product having a particular name, formulation, dosage form (i.e., physical presentation) and strength and with a particular set of approved indications
Table 3. Format of the ICH CTD and ACTD
Documents Format Differences
ICH CTD ACTD
Administrative documents and product information
Module 1 Part 1
Common Technical Document overview and summaries
Module 2 Incorporated in Parts 2, 3 and 4
Quality documents Module 3 Part 2
Nonclinical documents Module 4 Part 3
Clinical documents Module 5 Part 4
December 2014regulatoryfocus.org 4
and directions for use. Any change in these parameters may result in the need to submit an application to vary the existing product license or possibly obtain a new product license altogether.
There are two types of drug product licensing applications in Singapore: a new drug application (NDA) and a generic drug application (GDA), the latter for a drug that is essen-tially similar to a currently registered product in Singapore.
The submission process is conducted online through the Pharmaceutical Regulatory and Information System (PRISM). The application can be submitted using either the ACTD of ICH CTD format (see Table 6).
NDA Submissions
There are three types of NDAs in Singapore for chemical and biological entities (see Figure 1):
• NDA 1:� for the first strength of a product containing a new chemical or biological
entity (i.e., one that has not been registered in Singapore before)• NDA 2:
� for the first strength of a new drug product containing a new combination of registered chemical or biological entities; for a new dosage form; for a new route of administration; or for new indication(s), dosage recommendation(s) and/or patient population(s)
� for new drug products that do not fall under the requirements of NDA 1• NDA 3:
� for subsequent strength(s) of a new drug product that has been registered or submitted as an NDA 1 or NDA 2; the product name, pharmaceutical dosage form, indication, dosing regimen and patient population are the same as the NDA 1 or NDA 2
� The application is evaluated and assessed through one of the following proce-dures: full, abridged and verification evaluation
Generic Drug Application: There are two application types for a generic drug application
• GDA-1: For the first strength of a generic product• GDA-2: For subsequent strength(s) of the generic product that have been regis-
tered or submitted as a GDA-1. The product name and pharmaceutical dosage form shall be the same as that for the GDA-1.
Figure 1. Application Routes for Singapore Drug Registration2
Is Product Registered
Essen1ally similar to a current
Registered Product
First Strength of Product ?
Contains new Chemical/Biological En1ty?
NDA 1
Post Approval Process Sec1on
NDA 2 NDA 3
GDA 1
GDA 2
No No
No
No Yes Yes
Yes
Yes
Applica+on Routes for Singapore Drug Registra+on
December 2014regulatoryfocus.org 5
All information and documents supporting an application should be in English. Authenticated documents not originally in English should be translated.
Malaysia
Applications for registration of a new product in Malaysia are divided into the following categories:
• application for an innovator product (new chemical entity/biotech product)� applies to a new chemical or biological entity; new combination of existing
chemical/biological entity(ies); existing chemical or biological entity(ies) in a new dosage form; or existing chemical or biological entity(ies) using a differ-ent route of administration
• application for a generic product• application via the abridged procedure (for certain categories of over-the-counter
products and traditional medicines, e.g., antiseptics/skin disinfectants; lozenges/pastilles)
An application must include administrative data (Part I), quality data (Part II), safety data (Part III) and efficacy data (Part IV). Innovator product applications must include Parts I through IV (except for existing chemical or biological entity(ies) in a new dosage form, which require only Parts I and II, along with pharmacokinetic data). Generic product applications must include Parts I and II, and abridged procedure applications require Part I only.
The Drug Control Authority (DCA) accepts online submissions––only via http://www.bpfk.gov.my—and applicants must be registered with Suruhanjaya Syarikat Malaysia (SSM) or the Malaysian Registrar of Business (ROB). The product owner must authorize an applicant in writing before that person can be the holder of the product registration cer-tificate and be responsible for all matters pertaining to the registration of the product. An applicant is responsible for supplying up-to-date information for the application, supporting documents and updating DCA regarding any change in product/application, especially dur-ing the course of evaluation, and after product registration, especially if the information pertains to rejection/withdrawal or adds data on product efficacy and safety or current Good Manufacturing Practice (CGMP) compliance of the manufacturers (and repackers, if applicable). The application for registration requires a non-refundable processing fee.
A separate application is required for each product, such as different products having the same ingredients but made with different specifications (with respect to strength/of ingredients, dosage form, physical form, etc.) or by a different manufacturer.
Regulatory Review
Application review in Malaysia follows a queue system (see Figure 2). There are sepa-rate queues for different categories of products: new chemical entities (NCEs), biological entity(ies), generics (full procedure), abridged procedure pharmaceuticals (OTCs) and traditional products (see Table 7). If the product is meant for a serious or life-threatening disease, a priority review may be granted. An application for registration of an NCE or bio-logic product will be rejected if no required additional data are submitted by applicants within six months of the last correspondence; for all other products, 90 days is allowed for a response. An email is sent to applicants about DCA decisions regarding approved/
Table 6. Timelines for Singapore Reviews
Type of Review Process of New Drug RegistrationProcess of New Generic Drug Registration
Standard review • 270 working days • 240 working days
Accelerated or priority review (Drugs for public health problems/life-threatening conditions)
• 180 working days• Verification route: 60 days
• Verification route: 120 working days
• Comprehensive Economic Cooperation Agreement (CECA) route: 90 days
December 2014regulatoryfocus.org 6
rejected applications. A product registration number is assigned if the product satisfies all requirements of quality, safety and efficacy and is granted registration approval by the DCA. This is specific for that particular product only, and, accordingly, a product registration cer-tificate is issued implying the registration’s provisions, conditions and limitations. Written appeals to the minister of health or the director of pharmaceutical services must be made within 14 days from the date of the DCA notification on the outcome of the application.
Table 7: Time Required for Review of New and Generic Drugs in Malaysia
Type of Review New Drug Registration New Generic Drug Registration
Standard • For new drugs and biologicals, 245 working days
• For a full evaluation, 210 working days
Priority Review • Drugs for life threatening diseases, Approximately 180 working days
Abridged Not applicable • Single active ingredient: 116 working days
• Two or more active ingredients: 136 working days
Thailand
The registration of new drugs in Thailand is governed by ThaiFDA. The drug board conducts monthly meetings during which it gives recommendations or opinions for licensing and issues registration decisions regarding license approval, withdrawal or suspension. As per The Drugs Act, persons who wish to sell, produce or import drugs into the country must obtain a license from ThaiFDA, and only authorized licensees are qualified to apply for
Figure 2. Malaysia Drug Review Process3
Pre Submission of Registra1on Applica1on
Submission of Registra1on Applica1on and screening process
Data Evalua1on
Mee1ng of the Drug Evalua1on CommiJee
Mee1ng of the Authority
Rejec1on Approval Appeal
** Sample tes1ng
***Licensing Post-‐Registra1on Process
* GMP Inspec1ons
Regulatory Outcome
* Good Manufacturing Prac1ce (GMP) Cer1fica1on ** For natural products only *** Applica1on for Manufacturer, Import and/or Wholesale License
Na1onal Pharmaceu1cal Control Bureau First Edi1on, Jan 2013
Malaysia Drug Review Process
December 2014regulatoryfocus.org 7
product registration. Also, drug manufacturing plants must be CGMP compliant. The certifi-cate of product registration is valid for five years from the issuance date.
The drug registration process is carried out in two channels that differ in their degree of control and dossier submission.
1. registration of general medicines2. registration of Thai traditional medicines
Submission requirements for general medicines differ (see Table 8). For example, they are further classified as generics (whose registration requires only dossiers on product manufacturing and quality control, along with product information); new medicines (whose registrations require a complete set of product dossiers); and new generics (whose regis-trations require dossiers of bioequivalence studies in addition to the required dossiers for generics submission).
There is a two-year period of safety monitoring as per the amended registration proce-dure for new drugs adopted in August 1989. The new drug first receives approval for use only in hospitals and clinics for at least two years. The safety reports from hospitals and clinics are submitted to ThaiFDA to decide whether general marketing of the drug should be allowed. In the interim, new generic products have to pass bioequivalence studies. The study data are submitted to authorities as proof of product bioavailability with product information and quality dossiers.
Table 8. Review Time for New and Generic Drug Registration in Thailand4,5
Type of Review New Drug Registration New Generic Drug Registration
Standard review • 210–280 working days • 110 working days
Accelerated or priority review (Drugs for public health problems/life-threatening conditions)
• 100–130 working days • 70 working days
Figure 3. Thai Drug Review Process
Applicant
Applica1on
Pre-‐filling screening review
Review by Experts/Sub-‐CommiJee/CommiJee
Make Decision by FDA
Approved Revised Rejected
Completeness of Review
Technical Review
Thai Drug Review Process
December 2014regulatoryfocus.org 8
Regulatory Review
A one-stop service center has been established in Thailand for submission of applications that can be processed and approved within a short period of time. A fast-track pathway for emergent medicines such as neoplastics, HIV and tuberculosis drugs and antiviral vac-cines has been created to reduce the review time period from 280 working days to 130 working days (see Figure 3).
The Philippines
To ensure efficiency and harmonization of standards for new drug evaluation, the Philippines Bureau of Food & Drugs (BFAD) is authorized to adopt measures and methods addressing drug evaluation issues not otherwise addressed by earlier administrative and regulatory constraints. Applicants must submit a registration dossier in accordance with the ACTD format (see Table 9). The contents include administrative data, quality data and nonclinical and clinical data. An application for a pharmaceutical product already available in foreign markets is evaluated from the data submitted to the drug regulatory agency of the country where it is marketed. Other postmarketing data that supplement or serve as alternative measures for existing regulatory requirements without undermining domestic standards on drug product safety, efficacy and quality can be added to the application. Informational requirements under a new drug application summary include:
• proposed labeling text for the pharmaceutical product with appropriate information in summary and technical sections that supports the addition of any statement in labeling
• statement indicating the drug’s pharmacologic class and its scientific justification (clinical indications and therapeutic benefits)
• brief marketing history, including countries where the drug has been marketed or withdrawn for safety and efficacy reasons and also countries where applications are pending, if any
• summary of chemistry, manufacturing and controls section of application• human pharmacodynamic and pharmacokinetic bioavailability summary• microbiology summary (for anti-infectives only)• summary of application’s clinical data section• concluding discussion stating the drug’s benefit-risk considerations• discussions of proposed postmarketing/monitored release study after drug’s
approval
Table 9. Review Time for New and Generic Drug Registration in the Philippines6
Type of Review New Drug Registration New Generic Drug Registration
Standard • six to nine months • six months
Indonesia
In Indonesia, drugs are classified into three groups:1. new drugs, further divided into NCEs based on new indication and new route of
administration2. biological products3. generics
The drug registration application is submitted to the head of the National Agency of Drug and Food Control. To obtain distribution permission, a drug should fulfill the following criteria:
• convincing evidence of efficacy and adequate safety, proven through preclinical and clinical trials or other proof in accordance with development in the relevant scientific knowledge
December 2014regulatoryfocus.org 9
• quality that fulfills the production process criteria in accordance with CGMP or Cara Pembuatan ObatyangBaik (CPOB), specifications and method of analysis of all materials used in the finished product with proven documents
• labeling containing objective and complete information to ensure the drug’s proper, rational and safe use
Drug registrations are categorized into new drugs and variations of existing drugs (see Table 10).
New drug registrations are grouped into: • Category 1—new drug with new active pharmaceutical ingredient or new deriva-
tive, or new combination or biological product with new active ingredient or new combination or in a new preparation form
• Category 2—new drug with old composition in a new preparation form or new strength or a similar biological product
• Category 3—drug or biological product with old composition with:� new indications� new posology
• Category 4� copy drug with a trade name� copy drug with a generic name
• Category 5—other health equipment containing a drug (combination product)
Drug variation registrations are grouped into:• Category 6—copy drug that already has obtained a distribution permit with a
modification that already has been approved in Indonesia; these modifications and additions include:� preparation form with different posology or treatment method� dosage form� drug strength� drug composition� copy drug with trade name into copy drug with generic name or vice versa� Category 7—drug that has obtained a distribution permit with a modification
of label claim that influences drug safety• Category 8—drug that has obtained a distribution permit with modification of:
� supplement ingredient� specifications and/or method of analysis� stability� technology of production and/or manufacturing site
• Category 9—drug that has obtained a marketing authorization with a modification or addition to the packaging
• Category 10—drug that has obtained a distribution permit with:� label claim modification that does not influence efficacy, safety and quality� packaging design modification� factory name or permit holder name change� importer change� package size modification or addition� trade name change without any change of formula and package form or type
Table 10.Review Time for New and Generic Drug Registrations in Indonesia7
Type of Review New Drug Registration New Generic Drug Registration
Standard • 300 working days • 150 working days
Accelerated or priority review (drugs for public health problems/life-threatening conditions)
• Life-saving and breakthrough drugs: 100 working days
• Drugs already marketed in harmonized countries: 150 working days
• Drugs for exportation and drugs electronically transmit-ted: 80 working days
• Essential generic drugs for public health program: 100 working days
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The drug registration process consists of two stages: pre-registration and registration dos-sier submission.
Pre-registration for all of the above categories is conducted to decide the evaluation path and drug registration document completeness. Applicants are further notified about the result of pre-registration, which is binding.
Along with the drug’s registration, an applicant is required to pay an evaluation fee to the National Agency of Drug and Food Control.
Supporting documents required for the dossier are:• quality and technology documents to ensure the drug’s quality• preclinical trial documents describing the pharmacodynamics and pharmacoki-
netic profile as well as toxicity safety level and a preclinical trial report matrix• clinical trial documents that convincingly prove the finished drug’s efficacy and
safety in a compliance and clinical trial report matrix
Registration forms and documents should be in Indonesian or English. Labeling of OTC drugs or limited OTC drugs must be in Indonesian (see Figure 4).
Conclusion
ASEAN is one of the most successful regional pharmaceutical harmonization groups of developing nations and can be regarded as an example for other regions. ASEAN’s drug regulatory authorities and industry have been working very closely to develop a number of harmonized documents. The next step for ASEAN countries will be to focus on mutual recognition of pharmaceutical registrations and implementation of a harmonized place-ment system. These countries also are working toward accepting electronic ACTD dossiers beginning in mid-2015.
In spite of these harmonization initiatives, industry must define a clear regulatory strategy by looking at the target countries, different patent terms and extensions, data requirements and registration timelines, as these attributes can have a major impact on product marketing plans.
Figure 4. Registration and Evaluation Process: Indonesia
December 2014regulatoryfocus.org 11
References1. Southeast Asian Economic Outlook 2010. Organisation for Economic Cooperation and Development website. http://www.
oecd.org/dataoecd/50/20/46338931.pdf. Accessed 21 October 2014.2. Guidance on Medicinal Product Registration in Singapore. Health Sciences Authority website. www.hsa.gov.sg/content/
dam/HSA/HPRG/Western_Medicine/Overview_Framework_Policies/Guidelines_on_Drug_Registration/Guidance%20on%20Medicinal%20Product%20Registration%20in%20Singapore%202011%20%28Main%20Guidance%20Document%20Only%29.pdf. Effective 1 April 2011. Accessed 21 October 2014.
3. National Pharmaceutical Control Bureau. Ministry of Health Malaysia website. http://portal.bpfk.gov.my/index.cfm?menuid=4. Accessed 21 October 2014.
4. Pre-marketing Control/Licensing. Food Drug & Administration Thailand website. www.fda.moph.go.th/eng/drug/pre.stm. Accessed 21 October 2014.
5. Siriporn C. Drug Control and Registration. Presented 8 December 2010. www.conceptfoundation.org/files/meeting/14.%20Chawanon%20-%20Drug%20Registration%20Thailand.pdf. Accessed 21 October 2014.
6. Republic of the Philippines, Food and Drug Administration website. http://www.fda.gov.ph/industry-corner/downloadables/217-requirements-for-drug-registration. Accessed 21 October 2014.
7. Decree of the Head of National Agency of Drug and Food Control of Republic of Indonesia on Criteria and Procedure of Drug Registration. http://apps.who.int/medicinedocs/documents/s18009en/s18009en.pdf. Published 14 May 2003. Accessed 21 October 2014.
About the AuthorsRavi Varahalu is a regulatory professional with 12 years of industry experience at pharmaceutical companies including American Remedies, GSK and MakroCare. He specializes in designing market expansion strategies and assisting pharmaceutical compa-nies in registering products in emerging markets. Varahalu can be reached at [email protected]. Jairam Masetti is a research professional with nine years of experience in analytics for life sciences. He specializes in analyzing big data and assist-ing sponsors as well as internal regulatory teams. He can be reached at [email protected].
Cite as: Varahalu R, Masetti J. “The Southeast Asian Regulatory Environment for Pharmaceuticals (Part 1).” Regulatory Focus. December 2014. Regulatory Affairs Professionals Society.
© 2014 by the Regulatory Affairs Professionals Society. All rights reserved.
