Experience and Value of

CTD
- Singapores Experience
Jalene Poh, Regulatory Consultant
Health Sciences Authority, Singapore

26 April 2011 | Korea

AGENDA
Overview of ACTD and ICH CTD
Implementation of CTD

Background
Implementation process
Challenges
Follow-ups

Benefits/Value of CTD
Regulators perspective
Industrys perspective
Public / Patients

Drug Information Association

www.diahome.org

HSA Organisational Structure

HEALTH PRODUCT REGULATION GROUP

ORGANIZATION CHART
Group Director

(wef 1 Jan 2011)

Dy. Group Director

Group Directors Office
Advisors

Scientific Advisory
Quality
Assurance
Office

Pre-marketing

Clinical Trials

Pharmaceuticals & Biologics

International
Collaboration

Vigilance, Compliance &

Enforcement

Project
Management
Office

Policy, Legislation
&
Operations

Audit & Licensing

Service
Management

Tobacco Regulation

Vigilance

Compliance

Generics & Biosimilars

Legend
* Pharmacoeconomics & Drug Utilization

Enforcement
Division
Medical Device

Complementary Health
Products

Admin , Training
& PEDU*

Branch

Function

AGENDA
Overview of ACTD and ICH CTD
Implementation of CTD

Background
Implementation process
Challenges
Follow-ups

Benefits/Value of CTD
Regulators perspective
Industrys perspective
Public / Patients

Drug Information Association

www.diahome.org

Overview of ACTD & ICH CTD

The CTD provides a common format for the
preparation of a well-structured submission dossier
It provides a modular framework described in:
ICH Topic M4 (ICH CTD)
ASEAN guidelines on the Common Technical Document for
Registration of Pharmaceuticals for Human Use:
Organisation of the Dossier (ACTD)

According to the chosen format, the documents will

be group into:
4 parts (ACTD)
5 modules (ICH CTD)

Drug Information Association

www.diahome.org

Overview of ACTD & ICH CTD

ICH CTD Triangle

Drug Information Association

www.diahome.org

Overview of ACTD & ICH CTD

The main differences between these two formats are the
numbering and naming of the sections:
Documents

Location in
ICH CTD

ACTD

Administrative Documents &

Product Information

Module 1

Part I

Common Technical Document

Overview & Summaries

Module 2

Incorporated in Parts
II, III and IV

Quality documents

Module 3

Part II

Non-clinical documents

Module 4

Part III

Clinical documents

Module 5

Part IV

Drug Information Association

www.diahome.org

AGENDA
Overview of ACTD and ICH CTD
Implementation of CTD

Background
Implementation process
Challenges
Follow-ups

Benefits/Value of CTD
Regulators perspective
Industrys perspective
Public / Patient

Drug Information Association

www.diahome.org

Implementation of CTD
Background
Start of ASEAN harmonisation of pharmaceutical
product dossier
Revision of drug registration requirements
Alignment with international requirements to guide and
facilitate review

Implemented use of CTD format in submission

dossier in 2004
Several companies were already submitting their
registration dossiers in the CTD format prior to its official
implementation in Singapore

Drug Information Association

www.diahome.org

10

Implementation of CTD
Background
CTD format applies to:
New drug applications
Post-approval variation application
For products whose initial dossier was not in the ACTD or
ICH CTD format, the submission dossier would also need to
be organised in the ACTD or ICH CTD format

Drug Information Association

www.diahome.org

11

Implementation of CTD
Process
Implementation process
Seminar and dialogue sessions with industry groups were
held to brief industry on new registration requirements
New initiatives were rolled out in phases
Companies were given opportunities to clarify issues and
justify for waivers during pre-submission consultations
Ongoing tracking of implementation issues, and maintained
dialogue sessions with industry
Transition period prior to official implementation when
voluntary compliance with new data requirements (e.g. API,
BE data) was allowed
Submission checklists which provide guidance on specific
documentary requirements
Drug Information Association

www.diahome.org

12

Implementation of CTD
Process

Drug Information Association

www.diahome.org

13

Implementation of CTD
Challenges
Perceived as increased regulatory and documentary
requirements for industry
Early dialogue sessions (starting in 2003) to prepare
industry for upcoming changes
Early communications allow companies (and global office)
more time to prepare updated filing dossier format
Minimize impact on local resource by facilitating
submissions with use of checklists and by improving clarity
of the guidance

Drug Information Association

www.diahome.org

14

Implementation of CTD
Challenges
Internal staff to familiarize and gain in depth
knowledge of the revised requirements
Attended internal and external trainings including
attachments to other agencies using CTD format
Experience sharing amongst peers

Drug Information Association

www.diahome.org

15

Implementation of CTD
Follow-Ups
Launch of new guide was followed up shortly with an
online e-filing system in-built with CTD filing format
(PRISM) in June 2004

Drug Information Association

www.diahome.org

16

Implementation of CTD
Follow-Ups
Revised checklists for clarity (Apr 2011)

Drug Information Association

www.diahome.org

17

AGENDA
Overview of ACTD and ICH CTD
Implementation of CTD

Background
Implementation process
Challenges
Follow-ups

Benefits/Value of CTD
Regulators perspective
Industrys perspective
Public / Patients

Drug Information Association

www.diahome.org

18

Benefits/Value of CTD
Regulators Perspective
Required information are arranged in a specific
format and sequence which lead to ease of reference
and search of information
Facilitate review process as:
Reviewers can quickly ascertain which information are
missing
Required information can be efficiently located
Communications (e.g. queries) with applicants are made
easier with a common point of reference
Filing deficiencies can be easily and clearly laid out with
minimal ambiguity

Drug Information Association

www.diahome.org

19

Benefits/Value of CTD
Regulators Perspective
Guide evaluators in their review process by
highlighting the information required to support an
application
Allow easy sharing of information and discussions
amongst reviewers

Drug Information Association

www.diahome.org

20

Benefits/Value of CTD
Industrys Perspective
Global dossiers are commonly arranged in CTD
format
Allow local applicants to submit global dossiers instead of
expending time and resources (at both global and local
offices) to prepare a local-specific dossier
Facilitate earlier submissions with less time spent on
localization of the filing dossier

Drug Information Association

www.diahome.org

21

Benefits/Value of CTD
Industrys Perspective
CTD format outlines drug registration requirements
and enables filings in a systematic manner
CTD requirements which are applicable to most regions
help to streamline drug registration processes which in turn
aid in lowering cost of bringing a new product to market

Efficient use of limited resources with the use of a

harmonized dossier e.g. one office can prepare
submissions for several countries in the same
region

Drug Information Association

www.diahome.org

22

Benefits/Value of CTD
Public / Patients
Reduced submission lead time and improved review
process will in turn facilitate early access to
medicinal products for patients
Harmonised technical requirements will help to
ensure standards (quality) of medicinal products
approved across regions are consistent
Continued public access to safe, efficacious and good
quality essential drugs

Efficient use of resources for drug development and

filing dossier preparations can contribute towards
affordability of medicinal products

Drug Information Association

www.diahome.org

23

References
ASEAN CTD:
http://www.hsa.gov.sg/publish/hsaportal/en/health_products
_regulation/western_medicines/guidelines.html

ICH CTD:
http://www.ich.org/products/ctd.html

Guidance on Medicinal Product Registration in

Singapore:
http://www.hsa.gov.sg/publish/hsaportal/en/health_products
_regulation/western_medicines/guidelines.html

Drug Information Association

www.diahome.org

24

THANK YOU

25

Practical use of ICH CTD

in facilitating approval
of products by
prequalification
programme and beyond
Dr Lembit Rgo
Coordinator
Quality Assurance and Safety:
Medicines
Essential Medicines and
Pharmaceutical Policies
World Health Organization
Geneva, Switzerland
ragol@who.int

WHO has been supportive to CTD

since its beginning
Promoted CTD but considered local views for
implementation
CTD full implementation from 2001 when PQP started
was not considered feasible immediately
Thus, implementation in WHO Prequalification of
Medicines Programme (PQP) has been in phases
Close to CTD format first
Since 2010 going to full CTD implementation

New guidelines in 2010

1. Preparation guideline: Guideline on submission of
documentation for a multisource (generic) finished
pharmaceutical product (FPP): Preparation of product
dossiers (PDs) in Common Technical Document
(CTD) Format;
2. Quality guideline: Guideline on submission of
documentation for a multisource (generic) finished
pharmaceutical product (FPP): Quality part

Background
Previous generic guideline: Guideline on Submission
of Documentation for Prequalification of Multi-source
(Generic) Finished Pharmaceutical Products (FPPs)
Used in the Treatment of HIV/AIDS, Malaria and
Tuberculosis (2005)

2005-2011: policy/approaches to assessment change

continually over time due to harmonization efforts,
scientific advances, development of approaches
e.g. process validation and pharmaceutical
development approaches have changed dramatically
over the past 10 years

New guideline development process

A guideline updated according to current
requirements, and adopting CTD format, was
needed.
CTD formatting: (crafting of preparation document,
plus formatting of quality document) initial
draft
guideline populated with quality technical
guidance
- updated according to current practice

- including additional information on how to meet

the requirements
new draft

New guideline development process

Consultation process with PQP senior assessors plus PQP

applicants (26) new draft

External consultation process (formal Expert Committee

circulation)
final draft

Presentation to EC on Specifications for Pharmaceutical

Preparations in October 2010

Currently:
- Preparation of PD guideline adopted (will be presented to WHO
EB in May 2011 and printed after it)
- Quality guideline provisionally accepted for pilot use in PQP

45th Expert Committee on Specifications for

Pharmaceutical Preparations
Geneva, 18-22 October 2010

http://www.who.int/medicines/services/expertcommittees/pharmprep/en/index.html

1.2 Objectives
This guideline is intended to:
assist applicants on the preparation
of PDs for multisource products by
providing clear general guidance
on the format of these dossiers;
fully adopt the modular format
of the CTD as developed by ICH;
and
provide guidance on the location of
regional information (Module 1)
and other general data
requirements.

1.2 Objectives
This guideline is intended to:
assist applicants on the preparation
of the Quality Module of PDs for
multisource products by providing
clear general guidance on the
format of these dossiers;
fully adopt the modular format of
the Common Technical
Document - Quality (M4Q) as
developed by ICH; and
provide guidance on the technical
and other general data
requirements.
These measures are intended to
promote effective and efficient
processes for the development of
the PDs by applicants and the
subsequent assessment
procedures by WHO.

Introduction to the two documents

I: The preparation guideline
Assists applicants with the preparation of product
dossiers (PDs) for multisource/generic products by
providing general guidance on the format of these
dossiers;
Describes and adopts the modular format of the CTD
as developed by ICH;
Provides guidance on the location of regional
information (Module 1) and other general data
requirements.
Primarily addresses the organization of the information,
not the studies required.

Adapting the CTD for new drugs

to CTD for generic drugs

Regional
Admin
Information

Not Part of
the CTD

Module 1

Nonclinical
Overview

Module 2
Quality
Overall
Summary

Clinical
Overview
Nonclinical
Summary

Clinical
Summary

Quality

Nonclinical
Study Reports

Clinical
Study Reports

Module 3

Module 4

Module 5

The CTD

Introduction to the two documents

II: The quality guideline

This guideline:
assists applicants with the preparation of the Quality
Module of PDs for multisource/generic products by
providing general guidance on the format;
adopts the modular format of the CTD
provides guidance on the technical and other
general data requirements (including preparation of the
quality overall summary product dossiers (QOS-PD)).

Key changes from the previous

guideline
CTD format fully adopted

Updating of requirements
Elaboration of how to meet quality requirements,
including full elaboration on the three ways to submit
API data:
- CEP
- API Master File (APIMF)

- full API data provided in the dossier

Key changes from the previous

guideline
Reductions in requirements (as they were more stringent
than in ICH regions):
fewer batches required to establish the FPP shelf-life
process validation report for pilot batches no longer
required (replaced by uniformity demonstration for the biolot)

reduced process validation/pharmaceutical development

requirements for established generics

FPP batches to support the shelf-life

Complicated FPPs:
sterile products, metered dose inhaler products, dry
powder inhaler products and transdermal delivery
systems.
ritonavir/lopinavir FDC tablets and FDCs containing
rifampicin or an artemisinin.
Two pilot batches required
Uncomplicated FPPs e.g. immediate-release solid FPPs
(with noted exceptions), non-sterile solutions
One pilot batch and a second batch which may be
smaller (e.g. for solid oral dosage forms, 25 000 or
50 000 tablets or capsules) are required

Navigating through the quality guideline

Section 1: introductory information
Text includes bolded ICH M4Q text, and unbolded
additional WHO text
ICH M4Q text revised to use WHO terminology:
API/FPP, FDC, PD
Generally refers to BE instead of clinical batches
Presentation of the data is described for various
scenarios e.g. multiple APIs, multiple FPP strengths, coblistered FPPs, etc.

Quality document: quality summaries

QIS/QOS

Section 3: introduces the Quality information summary

(QIS)/Quality overall summary (QOS)
The instructions for the QOS-PD (Module 2.3) run
throughout the quality guideline
Instructions for the QIS (Module 1.4.2) are in Section
3.2 and preface the QIS template

Quality document: Section 4 module 3

Quality Data Sections

Section 4: QUALITY data in CTD format

Section 4 is divided (according to CTD structure) into:
3.2.S Drug substance (or API), and
3.2.P Drug product (or FPP)

Quality document: Section 4 module 3

Three options for API information:

1. CEP PhEur certificate of suitability
2. APIMF API master file
3. Full details in the PD

Quality Templates: QIS and QOS-PD

QOS-PD = Quality Overall Summary Product Dossier

The QOS is part of the ICH CTD structure of a product
dossier (PD). Replaces the PQIF (previous quality
template for PQP)
The QOS-PD is based on the CTD QOS,
modified/expanded to be of the most use to WHO

Implementation dates

PDs in CTD format can be submitted now but are

optional.
For all PDs submitted after 1 March 2011, the QOS-PD
and QIS are mandatory.
CTD format dossiers are encouraged at this time. They
are mandatory in PQP after 1 September 2011.

PQP experience in implementing CTD

The requirements were pretty close to CTD already

before final implementation of CTD was undertaken
Some applicants asked if they can submit CTD format
dossiers (which were accepted)
No complaints since full CTD implementation started
Transition period given - previous format still accepted
until October 2011

PQP experience in implementing CTD

assessors views
More difficult to "hide" missing data
Pushes manufacturers for more mature submissions with
better quality of data

Better structured format easier to assess

Easier to communicate with colleagues in the team, and
beyond

Benefits of the CTD experienced by

Less Resourced NMRAs

More reviewable applications

Complete, well-organized submissions
More predictable format
More consistent reviews
Easier analysis across applications
Easier exchange of information with other regulators
(harmonisation) and applicants (deficiency letters)
Facilitates electronic submissions

Recent African NMRA Experience

Background
The application forms and guidelines often old with no revisions
The application forms not in line with current practice
API information provided scanty, if at all
No information on product development was provided
There were many "briefcase" manufacturers that could afford to
compile dossiers overnight and submit
Many applicants based in SRA-regulated countries had to reorganize their applications to simplify the dossier and in some
instances excluded key data
Challenges
Legislation has to be changed and this is a huge task
Loss of revenue due to reduced number of applications (applications
number dropped!)
Managing the change stakeholders used to less documentation,
less stringent review processes, evaluation capacity
Involvement of stakeholders in the change process

ICH CTD implementation workshop

WHO continues to organize and

support CTD implementation trainings