Emerging Markets

The ASEAN Harmonization Scheme:

Another CTDAnother Challenge to the Industry
By Maha M. Lakkis, PhD, RAC

n keeping with the trend toward international and regional trade cooperation, several
regional pharmaceutical harmonization initiatives have been developed to establish cooperation
among involved countries to minimize efforts
and speed their access to new medicines. A typical harmonization initiative for the regulation of
drug registration is the International Conference
on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
(ICH), a tripartite collaboration of the regulatory
authorities of Europe, Japan and the US. Non-ICH
countries also have expressed the need to develop
a harmonization process, which has resulted in the
formation of these regional harmonization initiatives. One of the most successful and effective is the
ASEAN harmonization initiative. ASEAN means
Association of Southeast Asian Nations and includes
10 member states: Brunei, Cambodia, Indonesia,
Laos, Malaysia, Myanmar, Philippines, Singapore,
Thailand and Vietnam. ASEAN was established in
1967 to promote regional economical unity and
cooperation by establishing the ASEAN Free Trade
Area1 (AFTA). The strategic ASEAN partnership
has led to a pharmaceutical harmonization initiative
that complements and facilitates the objectives of
AFTA by enforcing cooperation in the area of public health and developing a harmonization scheme
of pharmaceutical regulations for ASEAN member
countries.

ASEAN Pharmaceutical
Harmonization Scheme
Efforts toward ASEAN pharmaceutical harmonization were initiated in 1992 by a proposal
from Malaysia to the ASEAN Consultative
Committee for Standards and Quality
(ACCSQ).2 Consequently the Pharmaceutical
Product Working Group (PPWG) was established in 1999. Its objectives were to develop a
harmonized scheme of pharmaceutical regulations
and establish a common technical document
and requirements to eliminate technical barriers
to pharmaceutical trade without compromising
safety, efficacy and quality.3 The PPWG began its

mission by reviewing the existing pharmaceutical requirements and regulations of the ASEAN
member countries, as well as other harmonization
procedures and international standards such as
ICH and World Health Organization (WHO)
guidelines. Throughout the development process,
the group communicated and consulted with
various international agencies and WHO. The
PPWG established consultation procedures that
are very similar to the Formal ICH Procedure and
applied ICHs procedures of drafting, consultation and adoption of final guidelines.4
The first organizational step was to agree
upon the three key topics for harmonization
quality, safety and efficacywhich are the main
criteria that form the basis of approval of all
medicinal products. Consequently, the ASEAN
common technical requirements for pharmaceutical product registration (ACTRs) and ASEAN
common technical dossier (ACTD) were developed. In addition, the PPWG established question and answer (Q&A) documents similar to the
ICH Procedure to support uniform implementation of the guidelines.5 The ACTD is intended
to be the standard marketing authorization application dossier accepted by all ASEAN member
countries, associated with the ACTD guideline
that provides information on the dossier structure
and format. The ACTRs are the set of written
guidelines intended to provide information on
dossier application content that meets the expectations of ASEAN drug regulatory authorities.
Each ACTR guidance includes a checklist that
cross-references the ACTD sections to the relevant accepted ICH guidelines or national pharmacopoeia. The responsibilities for coordinating
the different key area guidelines and corresponding ACTD sections were divided among the lead
countries as follows:6
ACTR/ACTD section on quality:
Indonesia
ACTR/ACTD section on safety:
Philippines
ACTR/ACTD section on efficacy:
Thailand

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ACTR/ACTD section on administrative

data, product information and glossary:
Malaysia
Guidelines on analytical validation:
Thailand
Guidelines on process validation:
Singapore
Guidelines on stability studies:
Indonesia
Guidelines on bioavailability (BA)/
bioequivalence (BE) studies: Malaysia

The PPWG adopted the ICH guidelines that

were applicable to the ASEAN region. Where
there was no existing guidance or if available guidance was not applicable to ASEAN, the members
developed their own. It was decided that clinical
and nonclinical studies should follow corresponding ICH guidelines and, for quality, the PPWG
adopted WHO guidelines, existing UK and US
Pharmacopoeias (BP & USP) and 11 ICH quality guidelines. In addition, four new guidelines on
analytical validation, process validation, stability
and BA/BE studies were introduced.
The need for an analytical validation guideline, especially for generic products, was recognized because at the time ASEAN requirements
were developed, no harmonized ICH guideline on
the topic was available. According to the ASEAN
Guidelines on Process Validation, three production batches typically should be validated before
final approval, allowing the review process to start
before the availability of the final report. But, the
applicant should provide a commitment at submission to provide the validation data before marketing the product. The analytical validation and
BA/BE guidelines are expected to be implemented
in January 2009.
However, the major change has been in stability requirements; the ASEAN stability guidance
was issued in February 2005, setting additional
stability study conditions (Zone IVb) for the
regions hot and humid conditions7,8,9 that go
beyond the established ICH Zone IV requirements

(Table 1). Thus, ICH Zone IV became known

as IVa. The new stability studies were adopted by
WHO, which amended its guidance on stability.8
They were also adopted by many non-ASEAN
health authorities not only for new applications
but also for renewals, making them contingent
upon meeting ASEAN stability conditions.

The ASEAN Common Technical

Dossier (ACTD)
The guidance on ACTD structure and format is
provided in The ASEAN Common Technical Dossier
(ACTD) for the Registration of Pharmaceuticals
for Human Use.5 This document is very similar
to the ICH M4 guideline,10 however, the ACTD
structure and format differ from the ICH CTD
in numbering, naming and granularity of sections. The ACTD organization guideline details
the recommended formatpaper size, fonts,
use of acronyms and abbreviations (similar to
ICH CTD)but the applicant is allowed to
modify it for the best presentation of technical
information. References should be cited in accordance with the 1979 Vancouver declaration on
Uniform Requirements for Manuscripts Submitted to
Biomedical Journals.
The ACTD is organized into four main
parts,5 each of which is subdivided into sections.
Part I: Table of Contents, Administrative Data
and Product Information
This part includes the following sections and
information:
Section A: Introduction
Section B: Overall Table of Contents (of
the whole ACTD)
Section C: Application form and ancillary
administrative documents (Certifications,
Letter of Authorization, etc), in addition to product information (labeling
and package insert); this section also
should include any information about the
pharmacologic class, mode of action, prescribed information, side effects, etc.

Table 1. ASEAN vs. ICH Stability conditions

Type of Container
Product in Permeable Package
Product in Impermeable
Container
Accelerated Stability

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ICH Zone IV (IVa) Requirements

ASEAN Zone IVb Requirements

30C/65% RH

30C/75% RH
30C/Ambient RH

40C/75% RH, 6 months

40C/75% RH, 6 months

50C (1 batch, 3 months)

Table 2. General Comparison of ACTD and ICH CTD

ASEAN-CTD

ICH-CTD

Part I: Table of Contents, Administrative Data and Prescribing

Information
Section A: Introduction
Section B: ACTD Table of Contents
Section C: Administrative Documents (Application Form,
Letters of Authorization, Certification Documents, Labeling,
Product Data Sheet, Prescribing Information, etc.)

Module 1: Administrative & Prescribing Information

1.1 Overall Table of Contents
1.2 Region-Specific Documents, Administrative Data &
Prescribing Information

Module 2: CTD Summaries

1.1 CTD Table of Contents (Modules 2-5)
1.2 CTD Introduction
1.3 Quality Overview
1.4 Nonclinical Overview
1.5 Clinical Overview
1.6 Nonclinical Written and Tabulated Summaries
1.7 Clinical Summary
Part II: Quality Document
Section A: Table of Contents
Section B: Quality Overall Summary
Section C: Body of Data (Reports)

Module 3: Quality
1.1 Module 3 Table of Contents
1.2 Body of Data
1.3 Published References

Part III: Non-Clinical Document

Section A: Table of Contents
Section B: Nonclinical Overview
Section C: Nonclinical Written and Tabulated Summaries
Section D: Study Reports (upon request only)

Module 4: Nonclinical Reports

4.1 Module 4 Table of Contents
4.2 Nonclinical Study Reports (Body of Data)
4.3 Published References

Part IV: Clinical Document

Section A: Table of Contents
Section B: Clinical Overview
Section C: Clinical Summaries
Section D: Tabular Listing of Clinical Studies
Section E: Clinical Study Reports (upon request only)
Section F: List of Key Literature References.

Module 5: Clinical Reports

5.1 Module 5 Table of Contents
5.2 Tabular Listing of all Clinical Studies
5.3 Body of Data (Final Reports)
5.4 Published References

The guidance, in addition, provides model templates for the application form (Appendix I),
Letter of Authorization (Appendix II), labeling
(Appendix IV), package insert (PI) (Appendix
V), product data sheet or summary of product
characteristics (SPC) (Appendix VI) and patient
information leaflet (PIL) (Appendix VII), as well
as information on specific certifications required
for different manufacturing situations.
Part II: Quality
Part II is subdivided into the following sections:
Section A: Part II Table of Contents
Section B: Quality Overall Summary
(QOS) and a checklist of information and
their respective location in the dossier.
Section C: Body of Data for the drug

substance (sections S1-S7) and drug

product (sections P1-P9). The Body of
Data subsection contents basically follow
the ICH Quality (Q) Guidelines, except
for the stability of drug product, which
should follow the ASEAN Guideline on
Stability Study of Drug Product, and the
analytical procedures validation, which
should follow the ASEAN Guideline on
Validation on Analytical Procedures.
Section D: Key Literature References

Part III: Nonclinical Document

This includes the nonclinical overview and
written and tabulated summaries. Full study
reports are not required if the product is already
approved in a major reference country, and they

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can be provided upon request by that health

authority. This part is subdivided into the following sections:
Section A: Part III Table of Contents
Section B: Nonclinical Overview:
1. Overview of the Nonclinical

Testing Strategy
2. Pharmacology
3. Pharmacokinetics
4. Toxicology
5. Integrated Overview and

Conclusions
6. List of Literature Citations
Section C: Nonclinical Written and
Tabulated Summaries
Section D: Nonclinical Study Reports, if
requested by ASEAN regulatory authority.
Section E: List of Key Literature
References
Part IV: Clinical Document
This should provide the clinical overview and
clinical summary. It is not required for generic or
minor variation products and some major variation products. Study reports are not required if
the original product is already approved in other
major countries and should be provided only
upon request by the health authority.
Section A: Part IV Table of Contents
Section B: Clinical Overview
Section C: Clinical Summaries
Section D: Tabular Listing of Clinical
Studies
Section E: Clinical Study Reports (only
upon request)
Section F: List of Key Literature
References.
According to the preamble of the guidance, the
ACTD is intended to ease implementation of electronic submissions. Currently, only a few countries
(e.g., Malaysia and Singapore) accept submissions
online via their own electronic submission systems (PRISM and QUEST, respectively). Parts of
the dossier are either typed in or uploaded to the
online submission system; the remaining documents are submitted as hard copy or on a CD.

General Comparison
of the ICH CTD and ASEAN CTD
In general, reformatting of information from
the ICH CTD into the ACTD is not straightforward, due to different section numbering,
pagination and cross-referencing. The areas of
similarities include the main topics and general

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content; the differences are mainly structural (see

Table 2). The main differences between ACTD
and ICH-CTD are:
The ACTD consists of four parts
(I-IV), with subsections A-F; the ICH
CTD consists of five modules with
numbered subsections.
The administrative data in Part I are an
integral part of the ACTD; Module 1 of
ICH CTD is country-specific.
Any additional data not contained in
the main sections of the ACTD should
be included as an addendum to the relevant section.
The quality (Part II), nonclinical (Part
III) and clinical (Part IV) summaries are
located at the beginning of each part of
the ACTD; the ICH CTD dedicates a
separate module (Module 2) for these
summaries. This is because the majority
of pharmaceutical products registered
in ASEAN countries are generics and
health authorities, therefore, primarily
review quality information. Therefore,
instead of separating the information
in two different dossier sections (e.g.,
ICH CTD quality overall summary in
Module 2 and detailed quality data in
Module 3), consolidating quality information under one section facilitates the
review.
For the clinical and nonclinical sections, only overviews and summaries
are required. Full reports may only be
submitted upon request.
The extent of granularity in the ACTD
is left to the applicants discretion,
whereas ICH dossier requirements are
more complex and well described in
M4R3 (Granularity Document).

Mutual Recognition Agreements

The PPWG developed a new initiative on
Mutual Recognition Agreements (MRAs) in the
Roadmap for Integration of Healthcare Sector11
to be implemented with the ACTR and ACTD.
The identified areas of MRA include:
MRA on the Postmarketing Alert
System (PMA): a postmarketing
alert system allowing the exchange
of safety data on marketed pharmaceutical products and supporting the
WHO International Medicinal Anticounterfeiting Taskforce Program. This
is intended to enhance Member States

pharmacovigilance capabilities via one

common reporting form and glossary.
MRA on Good Manufacturing Practice
(GMP) Inspections: aims at an agreement among ASEAN countries to accept
one anothers GMP inspection reports.
MRA on Bioavailability (BA) and
Bioequivalence (BE): aims to establish
one common ASEAN list of comparators that can be applied to generics for
the whole region, similar to the WHO
list of comparators. It also encourages
Member States to accept BE studies conducted by accredited national regulatory
authorities, and supports the notion of
BE center accreditation by national and
international regulatory authorities.

Conclusion
While submission teams in the pharmaceutical
industry are still working to fully understand and
improve the ICH CTD format for new drug applications, the ASEAN community came up with its
own new CTD format, the ASEAN CTD. This
additional dossier format to prepare adds another
challenge to the industry . However, the ACTDs
advantage is that one dossier can be prepared for
all ASEAN countries, reducing efforts and facilitating the regulatory review process.
The ACTD is not yet fully implemented
in all the ASEAN member states, especially for
NCEs and biologics. The implementation of the
ASEAN harmonization scheme took longer than
originally planned. After a trial period in 2003
and an attempt to implement it in January 2007,
implementation was postponed until January 2009
to allow member states regulatory authorities to
establish ACTD requirements. In the interim,
either formatASEAN or ICH CTDis
accepted. Some countries, e.g., Malaysia and
Singapore, have already begun requiring electronic filing online via structured electronic
systems (QUEST and PRISM, respectively)
configured to ensure the proper ACTD filing
format.
Attempts to harmonize labeling have not
succeeded so far and many country-specific
requirements remain; therefore, it is not currently possible to create one package usable in all
ASEAN countries.
ASEAN registration requirements place special emphasis on the quality data because the majority of the pharmaceutical products reviewed by the
regulators there are generics, so consolidating quality
information under one part facilitates the review.

Some training is still needed for both industry and regulatory authorities to ensure successful
ACTD implementation and evaluation. At this
early stage, applicants are encouraged to consult
with the appropriate national regulatory authorities to determine this formats applicability to
their particular drug application.
References
1. www.asean.org
2. www.aseansec.org/ACCSQ_structure.htm
3. www.aseansec.org/14904.htm
4. www.ich.org/cache/compo/276-254-1.html
5. www.aseansec.org/18215.htm
6. Zahn M. Developments from ASEANs ACCSQ
Pharmaceuticals Product Working Group. RAJ Vol. 12,
No. 12:985-987.
7. Stability Studies in Global Environment.
WHO Report, 2004. www.who.int/medicines/services/expertcommittees/pharmprep/
QAS05_146Stabilitywithcomments.pdf
8. Kopp S. Stability Testing of Pharmaceutical Products
in a Global Environment. RAJ Pharma Vol. 17, No.
5:291-294
9. Singh S and Kumar V. Recent Developments on LongTerm Stability Test Conditions. The Pharma Review.
December 2006: 61-68.
10. Organization of The Common Technical Document for the
Registration of Pharmaceuticals for Human Use, M4, ICH
Harmonized Tripartite Guideline. www.ich.org/LOB/
media/MEDIA554.pdf
11. Report of the Thirteenth Meeting of The ASEAN
Consultative Committee for Standards and Quality,
Pharmaceutical Product Working Group. 2527 July
2007. Kuala Lumpur, Malaysia.
Author
Maha Lakkis, PhD, RAC is a senior manager and liaison
in global regulatory affairs, managing drug registrations for
Schering-Plough Corp. in most of the world, including Latin
America, Asia Pacific and the Middle East. Lakkis began her
career as a scientific researcher at the University of Michigan
and the University of Pennsylvania. Later, she moved into
industry doing pharmacogenomics research before transitioning into US regulatory affairs. She holds a doctorate from
Florida State University.

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