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REGULATORY REQUIREMENTS FOR THE REGISTRATION OF GENERIC SOLID

Updated on June 6, 2016

The availability of generic medication is an important issue in the ASEAN region. The regulatory requirements of various countries vary from each other. Therefore it is challenging for the companies to develop a single drug which can be simultaneously submitted in various countries for approval. The role of regulatory authorities is to ensure the quality, safety, and efficacy of all medicines in circulation in their country. It not only includes the process of regulating and monitoring the drugs but also the process of manufacturing, distribution, and promotion. The regulatory environment has similar characteristics but drug registration requirements and processes differ among the countries. One of the primary challenges for regulatory is to ensure that the pharmaceutical products are developed as per the regulatory requirement of that country. This process involves the assessment of critical parameters during product development. Regulatory requirements and generic drug registration for USA and ASEAN regions is made at the end of the section. In ASEAN region documentation can be filed in the ACTD format. In US region documentation can be filled in the CTD/eCTD format.

Keywords: ASEAN, ACTD, ICH CTD, Documentation, Regulatory Authority

INTRODUCTION

The solid oral dosage form segment is the largest segment within the U.S. solid oral dosage forms market making up approximately 45.1% of this market11. This

segment is expected to grow from $4.8 billion in 2011 to

$5.9 billion by 2016 at a 4.1% compound annual growth rate (CAGR). Generics are expected to be a growth driver for this segment, with patents expiring for several drugs and companies looking to manage their portfolios and manufacturing capacity. A generic drug is a drug defined as "a drug product that is comparable to brand or reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use”. According to the U.S. Food and Drug Administration (FDA), generic drugs are identical or within an acceptable bioequivalent range to the brand-name counterpart with respect

to pharmacokinetic and pharmacodynamic properties1.

The ASEAN2 (Association of Southeast Asian

Nations) group of nations, [namely Indonesia, Malaysia, Philippines, Singapore, Thailand, Brunei Darussalam, Vietnam, Laos, Myanmar and Cambodia] is an eye catcher for most pharmaceutical companies due to the growing population and attractive pharmaceutical market growth.

ASEAN established the CTD so it is called as ASEAN Common Technical Document (ACTD) and the ASEAN Common Technical Requirements (ACTR) to create harmonized requirements and a common format for all submissions of dossiers in the ASEAN countries. The ACTR are a set of written requirements or guidelines intended to provide guidance to applicants in order to be able to prepare application dossiers in a way that is consistent with the expectations of all ASEAN Drug Regulatory Authorities (DRAs).

Dossier Format –ASEAN CTD

As mentioned before, the ASEAN countries established the ACTD as their format for submissions. It is a standard derived from the ICH CTD. The ASEAN CTD is a guideline of the agreed upon common format for the preparation of a well-structured ACTD application that will be submitted to ASEAN regulatory authorities for the registration of pharmaceuticals for human use.

The ACTD is similar to the ICH CTD. The ICH CTD is divided into 5 modules whereas the ACTD contains of 4 parts. The reason for doing this is the fact that the ASEAN countries normally receive a reference application, which is a dossier which was already approved in other countries in the world (mostly EU and USA) and make the evaluation of the parts mainly based on the overviews and summaries. Based on this, the need for detailed documentation is in most of the ASEAN countries is less compared to the ICH countries, e.g. most study reports are not required to be submitted. The Module 1 of the CTD containing the regional registration

h: 0px; "> and administrative information is still presented as Part 1
of the ACTD. The Module 2 of the CTD does not exist
itself for the ACTD. The Quality Overall Summary
(QOS) and the overview and summaries of the nonclinical and clinical documentation (similar like the
documents in ICH Module 2) are included at the
beginning of these Parts. Part II of the ACTD contains the
pharmaceutical-chemical-biological documentation (the
quality information), which corresponds to the ICH
Module 3.The non-Clinical information is presented as
Part III of the ACTD (equivalent to ICH Module 4) and
the clinical documentation is contained in Part IV of the
ACTD (to be consistent with ICH Module 5). The
differences between ICH-CTD and ACTD are presented
in the attached comparison pyramid.
MARKETING A DRUG PRODUCT IN USA3
To enter into the US market, the product will
need to get the approval from the US Food and Drug
Administration (FDA). The applicant files a market
application with FDA. After reviewing the application,
FDA will decide whether to grant the product approval.
Selling the product without the approval would make you
a felony under the US Federal Food, Drug and Cosmetic
Act. The FDA has approved following pathways:
1. The Abbreviated New Drug Application (ANDA),
2. Over-the-Counter (OTC) Monograph
3. The New Drug Application (NDA).
Generic Drug Product Registration Requirements in
US
1. The eCTD is mandatory for the submission of the
drug applications (NDA/ANDA).
2. US FDA guidance (CFR) documents and FDA
sections (e.g. 505 (b) for NDA and 505(j) for
ANDA) are followed for the preparation of the
dossier for the drug approval applications.
3. The applications are different e.g.
 For new drug- NDA
 For generic drug – ANDA
 For biological application – BLA
4. The application is directly submit to the FDA by the
applicant or through any approved contact agent for
whom a certification is provided to the agency
according to the GDEA 1992.
5. Administrative information is different i.e. cover
letter, forms (356h), application information, field
copy certification, debarment certification, financial
certification, Patent information and exclusivity.
6. The paper size for the submission is Letter size
(8.5x11 inches) with font size 12 in times new
roman format. The tables and figures have small
font size i.e. 8 to 10.
7. Package inserts are provided for drug product in
labeling.
8. Proposed Labels and cartons with proper
dimensions similar to that of the RLD labels are
provided.
9. The information about the clinical investigators is
provided in the Module 5 and in financial disclosure
Statement section of this module.
10. Request for waiver of in-vivo BE studies is provided
in the module 1.
11. Annotated draft labeling (side by side) for labels and
cartons compared with the RLD with proper
annotation is provided.
12. The EAS (Environment Assessment Statement) for
categorical exclusion certification in compliance
with the law of EPA of US is provided.
13. Risk management Plans section is for the post
marketing surveillance and controlling the adverse
effects of the drugs by proper management. This is
the part of Clinical Trial Phase IV.
14. The executed batch records for manufacturing and
packaging are provided in Module 3.2.R for only
single batch.
15. The declaration is given for the residual solvents
limits used or present in the drug substance and
excipients according to the USP.
16. Information on components including the name and
address of the supplier or manufacturer of the raw
material, package material etc. provided in the
3.2.R.
17. Letter of Access is not mentioned in 3.2.R.
18. Transmissible Spongiform Encephalopathy (TSE)
and Bovine Spongiform Encephalopathy (BSE)
certificates are not attached in this section whereas
submit in DMF.
19. Certificate of suitability (CEP certificate) is not
applicable.
20. Comparability protocols are not attached for both
the drug substance and drug products.
21. The stability data for accelerated studies are
submitted for three months at the time of original
submission.
22. Node extension is not allowed in the eCTD XML in
software.
23. Structured product labeling (SPL) and study tagging
file (STF) is mandatory by the USFDA in eCTD of
a drug registration application. Paper CTD format is
not accepted by FDA at all.
For the registration of generic drugs in USA we should
follow the ANDA regulatory review process.
ANDA Regulatory Review Process4
The ANDA process begins when an applicant
submits an ANDA to the OGD. The document room staff
process the ANDA assigns it an ANDA number, and
stamps a received date on the cover letter of the ANDA.
The ANDA is then sent to a consumer safety technician,
who reviews the preliminary sections of the ANDA
checklist. Within the first 60 days following the
submission of an ANDA, a filing review is completed
(Figure 1).
Regulatory requirements for registration of generic
drugs in Singapore5
Health Sciences Authority (HSA) is the
regulatory authority for regulating pharmaceutical
products in Singapore. For new product licenses,
Singapore has a new drug application (NDA) and a
generic drug application (GDA) for products already
approved by certain regulatory agencies (such as

h: 0px; "> and administrative information is still presented as Part 1
of the ACTD. The Module 2 of the CTD does not exist
itself for the ACTD. The Quality Overall Summary
(QOS) and the overview and summaries of the nonclinical and clinical documentation (similar like the
documents in ICH Module 2) are included at the
beginning of these Parts. Part II of the ACTD contains the
pharmaceutical-chemical-biological documentation (the
quality information), which corresponds to the ICH
Module 3.The non-Clinical information is presented as
Part III of the ACTD (equivalent to ICH Module 4) and
the clinical documentation is contained in Part IV of the
ACTD (to be consistent with ICH Module 5). The
differences between ICH-CTD and ACTD are presented
in the attached comparison pyramid.
MARKETING A DRUG PRODUCT IN USA3
To enter into the US market, the product will
need to get the approval from the US Food and Drug
Administration (FDA). The applicant files a market
application with FDA. After reviewing the application,
FDA will decide whether to grant the product approval.
Selling the product without the approval would make you
a felony under the US Federal Food, Drug and Cosmetic
Act. The FDA has approved following pathways:
1. The Abbreviated New Drug Application (ANDA),
2. Over-the-Counter (OTC) Monograph
3. The New Drug Application (NDA).
Generic Drug Product Registration Requirements in
US
1. The eCTD is mandatory for the submission of the
drug applications (NDA/ANDA).
2. US FDA guidance (CFR) documents and FDA
sections (e.g. 505 (b) for NDA and 505(j) for
ANDA) are followed for the preparation of the
dossier for the drug approval applications.
3. The applications are different e.g.
 For new drug- NDA
 For generic drug – ANDA
 For biological application – BLA
4. The application is directly submit to the FDA by the
applicant or through any approved contact agent for
whom a certification is provided to the agency
according to the GDEA 1992.
5. Administrative information is different i.e. cover
letter, forms (356h), application information, field
copy certification, debarment certification, financial
certification, Patent information and exclusivity.
6. The paper size for the submission is Letter size
(8.5x11 inches) with font size 12 in times new
roman format. The tables and figures have small
font size i.e. 8 to 10.
7. Package inserts are provided for drug product in
labeling.
8. Proposed Labels and cartons with proper
dimensions similar to that of the RLD labels are
provided.
9. The information about the clinical investigators is
provided in the Module 5 and in financial disclosure
Statement section of this module.
10. Request for waiver of in-vivo BE studies is provided
in the module 1.
11. Annotated draft labeling (side by side) for labels and
cartons compared with the RLD with proper
annotation is provided.
12. The EAS (Environment Assessment Statement) for
categorical exclusion certification in compliance
with the law of EPA of US is provided.
13. Risk management Plans section is for the post
marketing surveillance and controlling the adverse
effects of the drugs by proper management. This is
the part of Clinical Trial Phase IV.
14. The executed batch records for manufacturing and
packaging are provided in Module 3.2.R for only
single batch.
15. The declaration is given for the residual solvents
limits used or present in the drug substance and
excipients according to the USP.
16. Information on components including the name and
address of the supplier or manufacturer of the raw
material, package material etc. provided in the
3.2.R.
17. Letter of Access is not mentioned in 3.2.R.
18. Transmissible Spongiform Encephalopathy (TSE)
and Bovine Spongiform Encephalopathy (BSE)
certificates are not attached in this section whereas
submit in DMF.
19. Certificate of suitability (CEP certificate) is not
applicable.
20. Comparability protocols are not attached for both
the drug substance and drug products.
21. The stability data for accelerated studies are
submitted for three months at the time of original
submission.
22. Node extension is not allowed in the eCTD XML in
software.
23. Structured product labeling (SPL) and study tagging
file (STF) is mandatory by the USFDA in eCTD of
a drug registration application. Paper CTD format is
not accepted by FDA at all.
For the registration of generic drugs in USA we should
follow the ANDA regulatory review process.
ANDA Regulatory Review Process4
The ANDA process begins when an applicant
submits an ANDA to the OGD. The document room staff
process the ANDA assigns it an ANDA number, and
stamps a received date on the cover letter of the ANDA.
The ANDA is then sent to a consumer safety technician,
who reviews the preliminary sections of the ANDA
checklist. Within the first 60 days following the
submission of an ANDA, a filing review is completed
(Figure 1).
Regulatory requirements for registration of generic
drugs in Singapore5
Health Sciences Authority (HSA) is the
regulatory authority for regulating pharmaceutical
products in Singapore. For new product licenses,
Singapore has a new drug application (NDA) and a
generic drug application (GDA) for products already
approved by certain regulatory agencies (such as

Australia's TGA, the US FDA, etc.), submitting an abridged dossier is possible. Applicants submit an online application through PRISM (Pharmaceutical Regulatory and Information System) and also submit a CTD dossier. Application types

In applying for a newProduct License for a medicinal product in Singapore, there are two categories of applications: a new drug application (NDA) and a generic drug application (GDA):

GDA-1: For the firststrength of a generic chemical product.

GDA-2: For subsequent strength(s) of the generic chemical product that has been registered or has been submitted as a GDA-1. The product name and pharmaceutical dosage form shall be the sameas that for the GDA-1.

TECHNICAL DOCUMENTS REQUIRED

Administrative documents

  • Comprehensive Table of Contents
    • Introduction
  • Application
  • Labeling, Package Insert and Patient Information Leaflet
  • Approved Summary Product Characteristics (SPC) / Patient Information Leaflet (PIL)
  • Assessment Report from Reference Agencies
  • Description of Batch Numbering System
  • Proof of Approval
  • Authorization Letters
  • GMP Certification/Proof of GMP Compliance
  • Patent declaration
  • Declaration on rejection, withdrawal and deferral
  • Declaration for GDA verification
  • Registration status in other countries

ACTD & ICH CTD overview and summaries

The overview and summary documents are to be inserted into Module 2 of the ICH CTD or into the relevant sections in Part II, III and IV of the ACTD.

A completed Singapore Quality Overall Summary (SQOS) must also be inserted into Module 2, section 2.3 of the ICH CTD or Part II, section B of the ACTD, irrespective of whether an ICH or ACTD QOS has been included in the application dossier. SQOS must be named and dated by the applicant prior to submission. The electronic copy of the Singapore QOS should be in Microsoft Word format (Table 1).

Quality documents Body of Data

Drug Substance

  • Drug Master File (DMF)
  • Certificates of Suitability (CEP)
  • Control of Drug Substance (3.2.S.4)
  • Stability Data of Drug Substance (3.2.S.7)
  • Drug Product
  • Pharmaceutical Development (3.2.P.2)
  • Process Validation (3.2.P.3.5)
  • Control of Excipients (3.2.P.4)
  • Control of Drug Product (3.2.P.5)
  • Container Closure System (3.2.P.7)
  • Stability Data of Drug Product (3.2.P.8)
  • Product Interchangeability (3.2.P.9)
  • Blank Production Batch Records

Body of Data


Registration dossier

The complete dossier should be submitted within 2 working days afterthe PRISM application submission to prevent delays in processing of the application. The date of submission will be defined as the date when HSA receives the complete data set for the application.

Documents required for generic drug registration in Thailand6

The procedure of generic drugs registration is divided into 2 main steps:

Step1: Application for the permission to import or manufacture drugs ample intended to be registered.

  1. Application form to be completely filled by

authorized licensee

  1. Drug formula [active ingredients(s) only]
  2. Drug literature
  3. Drug labelling and packaging
  4. Application form to be completely filled by authorized licensee
  5. Permit to manufacture or import drug sample
  6. Drug sample
  7. Pharmacological and toxicological study (if any)
  8. Clinical trials, safety and efficacy study (if any)
  9. Complete drug formula
  10. Drug literature
    1. Labeling and packaging should consist of name of the drug, registration number, quantity of drug per packaging, formula which shows active ingredient (s) and quantity of strength, lot no. batch control number, name of manufacturer and address, manufacturing date, the words "dangerous drug"/"specially controlled"/ "for external use"/ "for topical use" written in Thai and in red color if the drug is considered to be one of them, the word "household remedy drug" written in Thai, if the drug is considered to be, the word "for veterinary use" written in Thai if the drug is considered to be, and the expiry date
    2. Certificate of Free sale (in case of imported drug)
    3. Manufacturing method
      1. In-process control with the relevant acceptable limits
      2. Raw material specifications of active(s) and inert ingredients with the corresponding control methods in details
      3. Finished product specification with the corresponding control methods in details
      4. Certificate of analysis of active ingredient (s) (raw material) [To be required in case of that active substance dose not conform to official pharmacopoeias (USP, NF, BP,……etc)
      5. Drug analytical control method
      6. Packaging
      7. Storage condition
      8. Stability studies of finished product
      9. Certificate of GMP (in case of imported drug)

Step2: Application for the approval of granted credential certificate.

a) FEES FOR APPROVAL

b) Registration fees = 12, 0000 Thai bhat (approx 4000 US$)

Regulatory Bodies in Malaysia7

  1. Ministry of Health Malaysia
    1. Drug Control Authority (DCA)
    2. DCA is the licensing authority.
  2. National Pharmaceutical Control Bureau (NPCB)

National Pharmaceutical Control Bureau (NPCB) of Malaysia is delegated the daily operations of drug registration and cosmetic notification, together with the attendant monitoring and surveillance activities. DCA is responsible for Registration of Pharmaceutical and Cosmetic products, Licensing of - premises for import, manufacturer, wholesale, monitoring the quality of product being market and adverse drug reaction in Malaysia (Figure


Requirements for generic registration8 Part I – Administrative data

Part II – Data to support product quality

Online Registration Procedure for Products

  1. Log into NPCB website (www.bpfk.gov.my) register as Quest member (as First-time User)
  2. After making payment to Digicert, within 7 working days (East Malaysia might take more time), Digicert will send the Digital certificate via POSLAJU. The login name and password will be emailed to the email address specified during the registration of Quest member.
  3. With the login name and password, enter Quest, go under registration, and register the product on-line. All forms are available in the form tray.
  4. Submit data requested
    1. Correspondences with NPCB officer if additional data is needed

Products tabled to DCA meeting.


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