REQUIREMENT DOSSIER SUBMISSION

IN INDONESIA

ISPE Indonesia Affiliate Annual Conference 2015

Dra. Nurma Hidayati, M.Epid.

Director Of Drug and Biological Products Evaluation
NADFC, Republic of Indonesia
Jakarta, 29 April 2015
 LEGAL BASIS IN INDONESIA

Badan Pengawas Obat dan Makanan RI..

2
Legal Basis - Indonesia
Law No. 36 of 2009 on Health
Law No. 35 of 2009 on Narcotics
Law No. 8 of 1999 on Customer Protection
Law No. 5 of 1997 on Psychotropics
Regulation of the Minister of Health No.1010/MENKES/PER/XI/2008 on Drug
Registration
Regulation of the Minister of Health No.1799/MENKES/PER/XII/2010 on
Pharmaceutical Industry
Decree of the Head of NADFC No. HK.03.1.23.10.11.08481 of 2011 on Drug
Registration
ACTD/ACTR Requirement & Implementation
Decree of the Head of NADFC No. HK.03.1.23.12.11.10217 of 2011 on
Mandatory Drug Testing Equivalences
Decree of the Head of NADFC No.3 of 2013 on Amendment of Decree of the
Head of NADFC No. HK.03.1.23.10.11.08481 of 2011 on Drug Registration
Legal Basis - Indonesia
Law No. 36 of 2009 on Health
Pasal 105, Ayat 1 :
Sediaan farmasi yang berupa obat dan bahan baku
obat harus memnuhi syarat farmakope Indonesia atau
buku standar lainnya

Yang dimaksud buku standar lainnya : US farmakope,

british farmakope, international farmakope
 PHARMACEUTICAL REGULATORY
FRAMEWORK IN INDONESIA

Badan Pengawas Obat dan Makanan RI..

5
 Pharma Regulatory Challenges
In Indonesia
Demand for greater access to new medicines which are
affordable to treat life threatening illness.

Ensuring safety, efficacy and quality of medicine as well

as accuracy and appropriateness of its labeling and
product information, while taking into account the
ASEAN harmonization efforts.

Ensuring consistency in Pre to Post Market Risk

Assessment by implementation of Good Regulatory
Practices from development, production, importation,
exportation and distribution to end-user
(patient/ consumer).

Badan Pengawas Obat dan Makanan RI..

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 Mandate for
The National Agency of Drug
and Food Control, Indonesia
(Presidential Decree No. 103/2001

The main mission: to promote and protect public

health by among other
Ensuring safety, efficacy and quality of medicine
according to the national and international standard

Facilitating easy access to affordable medicine regarded

having public health importance without compromising
safety, efficacy and quality

Badan Pengawas Obat dan Makanan RI..

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Regulatory Framework on Ensuring Medicine of
Assured Quality, Safety, and Efficacy

Medicine Quality Assurance Structural

Components

Assured Q, S, E of drug product

Documentation, Monitoring, and Evaluation
Regulatory Post-
Technical
Pre Elements marketing
Elements
Marketing (full spectrum/ control
(quality
Assessment comprehensive (for quality
specifications,
(marketing functions incl, and adverse
Basic tests,
authorization/ inspection, events, and
GMP, GLP,
licensing and recall, central product
GDP, GSP,
registration) & provincial information/
GCP)
lab) promotion)
Adequate legislation and law enforcement

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Phases Of Pharmaceutical Regulatory Framework In Indonesia:
System, Standard And Requirements
Development Over The Years

1970-2000 2000-2009 2009-.

Initial Phase Strengthening Phases Harmonization

Phase

Badan Pengawas Obat dan Makanan RI..

 Phases Of Pharmaceutical Regulatory Framework In Indonesia:
System, Standard And Requirements
Development Over The Years

1970-2000 1970 - 1920:

Initial Phase

Setting Up legislative Standard of Pre Approval

framework for pre-to post Review Process & GMP
market control-i.e. Compliance
Regulation on Drug
regulation &GMP

Badan Pengawas Obat dan Makanan RI..

 Phases Of Pharmaceutical Regulatory Framework In Indonesia:
System, Standard And Requirements
Development Over The Years

1980-1990 1990-2000 2000-2009 1980 2010:

Strengthening Phases

GRP (Good Regulatory Practices) Post-Approval:

Standards and Requirements
Pre-Approval:
Drug Registration
Production Standard &Requirement
(GMP)
Clinical Trial (GCP) & Clinical Trial
Authorization (CTA)
BA/BE Requirement
Labeling Requirement
Badan Pengawas Obat dan Makanan RI..
-Inspection on Production facility
(GMP) and Distribution Channel
(GDP)
-Pharmacovigilance on Data
Safetyvoluntary Reporting
-Post Market Control on Quality
Requirements (Good Sampling
Practices)
Organization aspects:
Reduce Bureaucracy, Consistent
interpretation and implementation,
transparency
REGULATORY SYSTEM ON DRUG REGISTRATION /
LICENSING IN INDONESIA (Pre Market Control)

Criteria &
Guidelines for
registration: Updated regulation on
- first issued in Based On Risk drug registration:
1980; Assessment To improve efficiency of the
Started - updated in: (Quality, Safety
process in anticipating Global
Harmonization trend
in * 1990, & Efficacy) and To accelerate drug evaluation
actual need of process without
1971 * 1993,
the public
compromising S, E & Q
GRP (Good Review
* 2000, health Practices)
* 2003, To provide a transparent and
efficient communication
* 2008, and stakeholders
* 2011
 LONG ROAD TO A NEW MEDICINE
Clinical Data
Analysis Registration
Delivery

Full Development
Candidate Medicine
Studies in 100 300 Tested in 3 10.000
patients (Phase II) patients (Phase III)

Extensive
Safety
Large Amounts of Studies
Candidate
Candidate Medicines
Studies in Healthy Synthesized
Formulations
Volunteers Phase I
Developed
Exploratory Development Early
Safety
Studies

Synthesis of Screening
Compound
Project Teams Discovery 13
and Plans
Registration Document:

The way words

are used : a document that
Document contains all the
Dossier technical data
CTD (administrative, quality,
nonclinical and clinical)
Information
of a pharmaceutical
Data
product to be
Body of approved / registered /
data
marketed in a country
Submission
Application
 THE GOALS OF THE DOSSIER

The goals of the dossiers are to provide enough information to permit

Regulatory Agencies reviewers to establish the following:
Is the drug safe and effective in its proposed use(s) when used as
directed, and do the benefits of the drug outweigh the risks?
Is the drugs proposed labelling (package insert) appropriate,
and what it contain?
Are the methods used in manufacturing (Good Manufacturing
Practice, GMP) the drug and the controls used to maintain the
drugs quality adequate to preserve the drugs identity, strength,
quality, and purity?
The content and format of the dossier must
follow rules as defined by the Competent
Authorities.

REGULATORY DOSSIER SUBMISSION IN ICH

COUNTRIES ICH CTD
REGULATORY DOSSIER SUBMISSION IN ASEAN -
ACTD
ASEAN Common Technical Dossier (ACTD) provides a common
format for the preparation of well-structured Common Technical
Dossier applications that will be submitted to ASEAN regulatory
authorities for the registration of pharmaceuticals for human use.
 General ASEAN Harmonization Issue

AC TD vs. ICH-CTD
Module 1 Non-
Similarity ---> Content Regional CTD
Admin.Info.
Part I
Differences ---> Organization
TOC ---> Numbering s ys tem Non-
Admin.data / Product clinical Clinical Module
Info. Quality Overview Overvie 2
Overall w
* = upon Summary Non-
request clinical Clinical
Part III Summary
Part II Part IV Summary
Non-Clinical
Quality Clinical
Overview, Module 4 Module 5
Overall Summary Summary, Overview, Module 3 Non-clinical
& Report & Study Summary,
C linical
Quality Study Study
Report* & Study Report* Report Report

Indonesia fully Implemented the AC TD/AC TR in January 2009

Friendly to ASE AN Members
Suitable & Facilitate the Evaluation/As s es s ment Proces s of majority Members
of ASE AN

Applicable to the main local product of ASE AN (Generic, and Modified Product)
OVERVIEW OF ICH CTD AND ACTD
Document ICH - CTD ACTD
Administrative Documents Module 1 Part I
and Product Information

CTD Overview and Module 2 Incorporated in parts II,

Summaries III & IV
Quality Documents Module 3 Part II
Non clinical Documents Module 4 Part III

Clinical Documents Module 5 Part IV

The summaries of the quality (Part II), nonclinical (Part III) and clinical
(Part IV) are located at the beginning of each part of the ACTD
 ASEAN HARMONIZED PRODUCT
ACTR ACTD GUIDELINES
(ASEAN COMMON (ASEAN COMMON and Q&A
TECHNICAL TECHNICAL
REQUIREMENT) DOSSIER)

GL on Stability Study
GL on Analytical
Technical Standard document Validation
Requirements on Q, for drug registration
GL on Process
E, S, Labeling / PI Submission of Validation
Admin. documents is GL on BA/BE Study
Relationship to according to ACTR GL on Efficacy and
GMP Safety (refer to some
implementation parts of ICH GL)
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Document with format of ICH-CTD

NADFC accepts the ICH-CTD format for product

registered in ICH countries and for local production that
want to register in ICH countries.

However, some certain section must follow the ACTR

requirement such as S tability studies must follow the
zone IV B (if applicable).
 E valuation of
S afety and E fficacy
Aspects
The Clinical Overview is intended to provide a
critical analysis of the clinical data in the CTD

describe and explain the overall approach to the clinical

development of a medicinal product, including critical study
design decisions
assess the quality of the design and performance of the studies,
and include a statement regarding GCP compliance
provide a brief overview of the clinical findings, including
important limitations (e.g., lack of comparisons with an especially
relevant active comparator, or absence of information on some
patient populations, on pertinent endpoints, or on use in
combination therapy)
The Clinical Overview is intended to provide a
critical analysis of the clinical data in the CTD

provide an evaluation of benefits and risks based upon the

conclusions of the relevant clinical studies, including
interpretation of how the efficacy and safety findings support the
proposed dose and target indication and an evaluation of how
prescribing information and other approaches will optimise
benefits and manage risks

address particular efficacy or safety issues encountered in

development, and how they have been evaluated and resolved

explore unresolved issues, explain why they should not be

considered as barriers to approval, and describe plans to resolve
them

explain the basis for important or unusual aspects of the

prescribing information
The Clinical Summary is intended to
provide a detailed, factual summarisation
of all of the clinical information in the CTD
 Evaluation on Quality Aspect (1)

Raw Material Development of Manufacturing

Drug Product
pharmaceutics Process

Reasons for the In Process Formulation

Source of raw
choice of Control (IPC) Specification
material
compositions, Process Excipients,
Synthetic route
constituents and Validation The container and
Specification
the containers Method closure
Analytical Dosing devices /
used Scientific Analysis
method delivery system, if
data generated to Validation
Stability any
support the Stability of
Active Bioequivalence (i.e :
choice Finished
Pharmaceutic for drug substance
Product with narrow
al Ingredient
Master File therapeutic therapy)
(APIMF)
Quality Document
QUALITY OVERALL SUMMARY
S. DRUG SUBSTANCE
S.1. General information
(Nomenclature, Structural formula,
General properties)
S. 2 Manufacturing process and
Manufacturer(s) (manufacturer,
description of manufacturing process
and process control, control of
material, controls of critical steps and
intermediates)
S.3 Characterisation
S. 4 Control of drug substances :
specification & analytical procedures
include validation of analytical
procedures, batch analyses, and
justification of specification
S. 5 Reference standards or
material
S.6 Container closure system
S.7 Stability
P. DRUG PRODUCT
P.1. Description and composition
P.2.Pharmaceutical development
Information on development studies
Component of drug product
Finished product
Manufacturing process development
Container closure system
Microbiological attributes
Compatibility
P.3 Manufacture In Situ
Batch formula
Manufacturing process and process control
Controls of critical steps and intermediates
Process validation and/or evaluation
P. 4 Control excipients :
specification and analytical procedures
P.5 Control of finished product :
specification, analytical procedures, validation of analytical
procedures, batch analyses, characterization of impurities,
justification of specification
P. 6 Reference standards or materials
P.7 Container closure system
P.8 Stability
P.9 Product interchangeability/equivalence evidence
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Active Pharmaceutical
Ingredient
New Quality Requirements

Information About API (S1 S7) is

required since 2008 in line with
ASEAN Common Technical
Requirement (ACTR)

Active Pharmaceutical Ingredient

Master File (APIMF) requirement for
all API as stated in Decree of the Head
of National Agency of Drug and Food
Control No. HK.03.1.23.10.11.08481 of
2011 on Criteria and Drug Registration
Procedure

GMP of API Manufacture

Drug Substance

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 Key Aspect of API

- Structure and characterization

- Physicochemical properties
- Manufacture
- Impurities
- Controls
- Reference Standards
- Containers and closures
- Stability

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 S.2 Manufacture of API
Starting material
for synthesis

Detailed
information Reaction
intermediate(s)
provided in
dossier
API starting
material
GMP
compliance
API intermediate(s)

Final API

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DRUG MASTER FILE (FDA)
Type of Drug Master Files :
Type I : Manufacturing site ,Facilities ,Operating
Procedure and Personnel
Type II : Drug substance , Drug substance
Intermediate and Material used in their
preparation or Drug Product
Type III: Packaging Material
Type IV : E xcipient, Colorant, Flavor, E ssence or
Material used in their preparation
Type V : FDA Accepted Reference Information

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API MASTER FILE
Reference Guideline on Active Pharmaceutical
Ingredient Master File (APIMF) Procedure ( does not
apply to biological APIs)
(http:/ / apps.who.int/ prequal/ info_applicants/ Guidelines/
APIMF_Guide.pdf)
Isi dari APIMF adalah informasi scientific ,yang terdiri
dari 2 bagian :
Open part , berisi informasi yang oleh APIMF holder
dianggap non- confidential bagi applicant /
Product Dossier holder
Restricted part , berisi informasi yang oleh APIMF
holder dianggap bersifat confidential

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APIMF/DMF Implementation
One of the following options to provide data on AP I :
1. A Valid quality Certificate of S uitability of E uropean
Pharmacopeia (CE P )
With all appendices
P rovide information, which may not be covered by the C E P

2. An AP IMF (AP I Master File)

S ubmitted by AP I manufacturer
C ontains all information requested in section 2.S . Drug
substance

AP IMF submission
127 Active ingredients from 203 manufacturer
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Contoh Website yang dapat membantu mencari produsen bahan
baku dan bahan baku yang telah listing
DMF Website
 List of DMFs
http://www.fda.gov/cder/dmf/index.htm
Updated quarterly
Contains additional information about DMF

FDAs DMF Webs ite

 Decree of the head of NADFC no.3
Year 2013
Amendment of Decree of the Head of NADFC
No. HK.03.1.23.10.11.08481 of 2011 on Drug
Registration

Consist of:
Registration for product using INN names

Approvable Letter
 Amendment of Decree of the Head of NADFC
No. HK.03.1.23.10.11.08481 of 2011 on Drug Registration

Registration for product using INN names (generic):

Should have the same spesification and quality with the
branded product or vice versa produced by the same
manufacturer, covering size, shape, colour, odor, and
flavour.
On the label/package: put information of ceiling price
and generic logo according to the prevailing regulation

For drugs registered more than one strength: put the

strength of API after dosage form, on the label
To ensure the stability of drugs in solid oral dosage forms,
drug registration packed with bottles contain at most 100
(one hundred) dosage (for drug with stable active ingredient)
 Requirement on Equivalence Study
(Decree of the Head of The NADFC dated 30 December 2011)

Equivalence Study:
Comparative Dissolution Test
Bioequivalence Study
Required for : 10 therapeutic classes (89 active substances) + modified
release drug
Implementation :
Copy/generic drugs:
In registration process
New registration
Renewal
Transition period :
Within 2 years, the applicant can submit Comparative Dissolution test
report, with commitment to submit Bioequivalence Study report at the
latest 3 years after the issuance of the decree.
APPROVABLE LETTER SYSTEM
 BACKGROUND

Number of approved drug = 19.483* item (*include different

strength & presentation)
Number of distributed drug based on a survey = 12.552 item
Percentage of distributed drug vs. approved drug = 64,43%

Number of active ingredient Pharmaceutical

Distributed : 926 items (269 active ingredient, 14 Industry 204
therapeutic class
Approved : 1108

On site evaluation shows disparities on drug formulation

during development phase compare to commercial
production
Lack of drug development data
> 90% of renewal applications are parallel with formulation
and labeling changes
> 75% of variation applications are formulation and labeling
changes.
 Yes DRUG REGISTRATION AND
Comply? EVALUATION FLOWCHART
No National Committee on
Legends:
Drug Evaluation
Pre Registration
Consultation Evaluation on safety and efficacy
Pre -Non klinik Registration
Registration - Pharmacodynamic
- Pharmacokinetic SMF Evaluation
Result
Pre - Toxicity Rejection/Appeal
Registration - Immunogenicity
- Clinic Additional Data
- Phase I, II, II
New Drug and - Phase IV (optional)
Drug
Biological Prod
registration - Abreviated Safety and efficacy
Applicant data
Yes
- Bioequivalence
Labelling
Comply?
Complete

Evaluation on Quality evaluation

Not

Active pharmaceutical ingredient

Complete

Source
Synthesis No
Data Specification
Completeness Analytical method Approva
MA
Assessment Stability ble Letter
Drug Product
Formula
Specification
Copy / Generic Analytical Method Validation
Drug Process validation Rejected Additional
Additional data Analytical method Data MA
Stability
Appeal

Yes

SMF data for Pre inspection Yes

document Comply? Inspection Comply?
import drug *)
evaluation
No No

*) Pharmaceutical Industry should be inspected

Approvable letter
Purpose :
To ensure that marketed drug produces using high quality
ingredients.
Documentation that submitted by the applicant for
registration is consistent with documentation to produce a
commercial scale

Benefit for applicant:

To prepare a commercial scale production (make approve
labeling and product information).
To reduce a variation submission after issuance of Marketing
Authorization .
To reduce timeline for drug application
 APPROVABLE LETTER
Notification of approval to the
applicant for preparations a
commercial-scale production
In situ evaluation carried out
during the first batch
commercial scale production
by considering the track
record of the manufacturer
(if necessary).
 APPROVABLE LETTER for IMPORT
PRODUCT
Notification of approval to the
applicant for preparation of drug
importation before issuance of
Marketing Authorization.
4 Industries had been ein situ
evaluation
Approvable letter
Approvable Letter is not a substitute for marketing
authorization.

Approvable Letter valid for 2 (two) years since the date of

issued.

Marketing of authorization will be issued if commercial

scale production pass all the requirement or provide proof
of importation

47
 APPROVABLE LETTER
for Local Production

applicant

incomplete

Pra registration registration applicant

complete
Product development
data, Packaging 100 WD
design
, Approvable
Letter Valid for 2 years
Packaging design,

production schedule for first

batch production
First batch produced On S ite E valuation (if
in comercial scale necessary)
Batch record, comparation on
result of commercial scale and
product development 20 WD

Marketing
Authorization
 APPROVABLE LETTER
for import product

applicant

incomplete

Pra registration registration applicant

Safety, Efficacy,
complete quality data, complete
Packaging design,

Approvable Letter Valid for 2 years

Packaging design, proof

of importation 20 WD

Marketing
Authorization
Marketing authorization will be issued if the commercial-
scale drugs meet all the requirements,e.g :

1. Produced in site that comply to cGMP

2. The production meets the established requirements as
evidenced by documents :
Commercial scale batch record including in process control
data, release of batches and process validation report
Quality comparison data results of commercial scale batch
versus product development
Importation document (for imported drug)

50
Implementation
Since February 2013
Feb 2013 - March 2015 : 877 Aprovable
Letter from 98 Industry
Approval of a marketing authorization has
been issued : 314
A total 77 products from 51
pharmaceutical industries have been
performed in-situ assessment
Expired Approvable letter: 45
In situ findings that cause delay in
marketing authorization

1. Lack of product development data

2. Formula different between development
data versus commercial scale that have
significant change in quality
3. Change of API Source
4. Stability of development data is still on
going
5. Bioequivalence evaluation is still on
going
 CONCLUSION
Premarket evaluation needs dynamic regulatory
pharmaceutical framework without compromising on safety,
efficacy, quality and public health need.

New aspects to be considered in evaluation process include:

On Site evaluation at the facility of product manufacture,
Active Pharmaceutical Ingredients Master File (APIMF), GMP
API.

Regulatory commitment on the consistency of

implementation of Good Regulatory Practices is the key to
anticipate regulatory challenges.

Pharmaceutical company: anticipated on development of

new technologies and related regulation

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