Indo American Journal of Pharmaceutical Research, 2021 ISSN NO: 2231-6876

A REVIEW: COMPARATIVE STUDY IN CTD DOSSIER FOR US, EU AND AUSTRALIA

MARKET
Rushikesh B. Katkar1*, Dr. Rajkumar S. Bagali2, Amar S. Kulkarni3, Chandrashekhar V. Babar4, Pooja
P. Patel5
1
Vijayarao Naik College of Pharmacy, Kankavali, Maharashtra.
2
Ashokrao Mane College of Pharmacy, Pethvadgaon-Kolhapur.
3,4,5,
Vijayarao Naik College of Pharmacy, Kankavali, Maharashtra.
ARTICLE INFO ABSTRACT
Article history This topic aims at reviewing the drug and drug product for filing and obtaining USFDA
Received 28/10/2021 EMEA and TGA approval and its effective role to improve the standards which are laid by
Available online them. The respective Regulatory Agency approves the new/generic drug products that govern
30/11/2021 respective market before introduction of particular product into the market. The Regulatory
Agency approves the entire new drug product to be safe and effective before marketing.
Keywords USFDA is the Regulatory Agency which is responsible for the regulation of food and drug
Dossier Registration, product in USA. EMEA is the Regulatory Agency which is responsible for the regulation of
CTD, food and drug product in Europe. TGA is the Regulatory Agency which is responsible for the
USFDA, regulation of therapeutic goods in Australia. A dossier contains detail information about the
EMA, drug substance and drug product and result of studies that are carried out in development
TGA. process. For getting market authorization has to be submitted to the respective regulation
bodies.CTD provides standardized structure. CTD makes filing easier globally. But there are
differences in dossier submission requirements in these countries i.e. Module I is country
specific and other regional guideline are also considered while compiling dossier application
and Processing.

DOI NO: 10.5281/zenodo.5746826

Corresponding author
Rushikesh B. Katkar
Assistant Professor
Vijayarao Naik College of Pharmacy,
Kankavali, Maharashtra.

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Please cite this article in press as Rushikesh B. Katkar et al. A Review: Comparative Study In CTD Dossier for US, EU And
Australia Market. Indo American Journal of Pharmaceutical Research.2021:11(11).
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Copy right © 2021 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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INTRODUCTION
CTD is a set of specification for a dossier for registration of medicines. CTD was developed by International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceutical for Human Use (ICH). CTD was developed by
European Medicine Agency (EMA, Europe), Food and Drug Administration (FDA, US) and Ministry of Heath, Labour and Welfare
(Japan). It was adopted by TGA in 2004. (1)
The agreement to assemble all the Quality, Safety, and Efficacy information in a common format (called CTD) has
revolutionized the regulatory review process led to harmonized electronic submission that in turn enabled implementation of good
review practices. For industries, it has eliminated the need to reformate the information for submission to the different ICH Regulatory
Authorities.
In July 2003, CTD became mandatory format for New Drug Application in Europe and Japan and strongly recommend format
of choice for NDAs submitted toFDA, US. (2)

CTD is organized into 5 modules-

Module 1- Administrative section (not a part of CTD as it is regional specific)
Module 2- Quality overall summariesModule 3- Quality
Module 4- Non Clinical Study ReportsModule 5- Clinical Study Reports
Module 1 is region specific and Module 2, 3, 4, 5 areintended to be common for all regions.

CTD TRIANGLE

Figure 1. The CTD Triangle.

The brief contents of CTD and major requirements for various regions are tabulated.

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Table 1 Difference of CTD structure in US and Australia.

US CTD AustraliaCTD DESCRIPTION REMARKS

Module 1-Module 1-Contains documents that are specific to each region. ThisRequired for andgeneric
Administrative Administrative module is not a part of CTD. . New Drug
Information Information and
Prescribing Information
Module 2- Module 2- This module summarizes the Module 3, 4 and 5. It includes Required for generics and
CTD Summaries CTD Summaries Quality Overall summary, Non Clinical Overview andNew Drug. For generics
summary and Clinical Overview and summary. Thesummary on Quality part only
summary provides reviewer the abstract of documentsrequired.
provided in the whole application.
Module 3-Quality Module 3-Quality The documents related to Chemistry, Manufacturing andRequired for andgenerics
Control of both Drug Substance and Drug Product areNew Drug
included in this module.
Module 4- Module 4- Non Clinical Study Reports- Data on pharmacologic, Not required for
Non- study Non- clinicalstudy pharmacokinetic, and generics.
clinical reports
reports

In CTD format, harmonizing the quality information mainly includes Chemistry Manufacturing and Control (CMC) that is to
be submitted in an application format. C: Chemistry means Composition of drug product. M: Manufacturing means how to
manufacture the product/formulation. C: Control means ensures whether the drug products meet the predetermined
specification/quality attributes.

Importance of CMC Section in CTD Dossier

 For any marketing application or clinical trials CMC (chemistry, manufacturing and controls) section is a very important and
detailed section.
 If the manufacturing process cannot be shown to its highest quality standard and do not satisfied the regulators need as well as
product have not their quality standard as mentioned in Pharmacopoeia than it might be chance to drug may lost the marketing
approval.
 So it is important to show the standard quality process and parameter of drug manufacturing details and other parameter cover in
module 3 Quality contain Chemistry, manufacturing and Control.
 The chemistry, manufacturing and controls (CMC) section is a very important part of any clinical trial or marketing application.
Drugs can be denied marketing approval if the quality of the product and the manufacturing process cannot be shown to be of a
sufficiently high standard to satisfy regulators.
 The ICH guideline Q1A(R2) (Stability Testing of New Drug Substances and Products) defines the stability data package required
for new drug substances and products submitted for approval in each of the major regions that accept the ICH guidelines (i.e., US,
Japan and EU). (3)

Common Dossier deficiency in CTD (3,4)

Queries in USA and EMEA
 The Qualitative & Quantitative certificate of a colorant needs to be appropriately provided.
 Polymorphism, Stereochemistry, Isomerismstudies and discussion on the drug substanceused in formulation is absent.
Although preservatives are used, microbial limit tests and such other information are not provided in the pharmaceutical
development data or later in the commercial scale batch manufacturing specifications.
 PDR (Pharmaceutical development reports) arenot complete.
 The development report should be prepared bytaking QbD into consideration.
 Pathogen Count and Total Count not provided.
 Genotoxic impurities needs to be studied whichmay arise from the Drug product.
 Existence/absence of polymorphism.
 TSE/BSE declaration is not provided for thesensitive Excipients.
 The spectral data such as IR, NMR, Elemental Analysis, XRD as a means for evidence of chemical structure is not provided.
 API: Spectral graphs for IR, NMR, UV Spectra studies performed are not clear and interpretation of the same is incomplete.
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 Acetone, Methanol and IPA have been used in the synthesis. However, these solvents are not analyzed for chance contamination
of Class I solvents from which they are prepared.
 For the synthesis of the API products, Class I solvent Benzene is used. But the residual limits for the same are not checked at any
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point.
 The catalysts such as Palladium/Platinum are used in the synthesis of the products. The residual limits for the same are not
described.

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Queries and Responses in Australia

Control of excipient:
Query-
The finished product manufacturer’s acceptance specification for hypromellose includes acceptance limits for all substitution
types (1828, 2208, 2906 and 2910) but the COA indicates that the criteria for substitution type 2910 (methoxy group: 28.0 – 30.0%;
hydroxypropoxy group: 7.0 – 12.0%) are applied.

Response-
Please amend the specification for hypromellose to include the acceptance criteria for the type of hypromellose used in the
proposed formulation (substitution type 2910), unless otherwise justified.

Finished Product Specification:

Query-
BP identification test by IR used for identification of the active ingredient in the drug product at release is acceptable.

Assay:
Query-
The proposed limits for content of Product X at release and ‘stability’ (95.0 – 105.0 % LC) comply with the BP monograph
requirements, as specified by TGO78. However, the application of common release and expiry limits does not take into account
any decreases that may be observed during long term storage of the tablets. In this respect, a tighter lower limit should be applied at
batch release to ensure that a tablet batch released with an active ingredient content at the lower limit complies with the limit of 95.0%
LC following full term storage at the maximum recommended storage temperature (30°C).

Impurities:
Query-
The proposed specifications for related substances (impurities A, B & G: NMT 0.3% each; any other impurity: NMT 0.2%;
and total impurities: NMT 1.0%) comply with the BP monograph requirements and are therefore acceptable for expiry purposes.

Validation of Analytical Parameters:

Query-
In relation to the validation of the Product X assay method, related substances method, and dissolution method intermediate
precision not provided.

Stability
Query-
Since the proposed finished product specifications include criteria for water content, the stability protocol should be amended
to include testing for water content.

Regulation for filing Drug Product in USA

In the USA, all the food, drugs, cosmetics and medical devices for both humans and animals are regulated under the authority
of the United States Food and Drug Administration (USFDA). USFDA acts as public health protector in United States and ensures
that all drugs in the market are safe and effective. (5)

New Drug Application (NDA)

For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application
(NDA). Since 1938, every new drug hasbeen the subject of an approved NDA before U.S. commercialization. The NDA application is
the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the
US. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the
NDA.
The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decisions:
 Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.
 Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.
 Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve
the drug's identity, strength, quality, and purity.
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The documentation required in an NDA is supposed to tell the drug's whole story, including what happened during the
clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is
manufactured, processed and packaged. (6)
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Figure 2. New Drug Application (NDA) (7)

Abbreviated New Drug Application (ANDA):

An abbreviated new drug application (ANDA) contains data which is submitted to FDA for the review and potential approval
of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe,
effective, lower cost alternative to the brand-name drugit references.
A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of
administration, quality, performance characteristics, and intended use. All approved products, both innovator and generics. Generic
drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical
(human) data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is
performs in the same manner as the innovator drug.

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Figure 3. Abbreviated New drug Application (ANDA) (7)

Regulation for filing drug product in Europe

The European Medicines Evaluation Agency (EMEA) was established in London, in the year 1995, to coordinate the
European Union (EU) member states for evaluating and supervising the medicinal products for both human and veterinary use. It
introduced a transparent procedure for the development, consultation, finalization and implementation of pharmaceutical guidelines.
The drug approval process in European countries is accomplished in two phases:

Clinical trial.
Marketing authorization.
A clinical trial application (CTA) is filed to the competent authority of the state to conduct the clinical trial within European
Union (EU). The competent authority of that member state evaluates the application. The clinical trials are conducted only after the
approval. Marketing authorization application is filed only after all the three phases of clinical trials are completed.

In European countries, there are four regulatoryprocedures:

(A) Centralized procedure;
(B) Decentralized procedure
(C) National procedure
(D) Mutual recognition procedure.

Centralized procedure
The centralized procedure is one which allows applicants to obtain a marketing authorization that is valid throughout the EU. (8)
 Results in a single authorization valid in EU, Norway, Iceland and Liechtenstein.
 Application evaluated by an assigned authority.
 Timeline: EMA opinion issued within 210 days, and submitted to European Commission for final approval.
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Centralized process is compulsory for:

 Those medicines which are derived from any biotechnology processes, such as genetic engineering.
 Those medicines which are intended for the treatment of Cancer, HIV/Aids, diabetes, neurodegenerative disorders or autoimmune
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diseases and other immune dysfunctions.

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Decentralized procedure
Using this procedure, companies may apply for authorization simultaneously in more than one EU country for products
that have not yet been authorized in any EU country and essentially do not fall within the centralized procedure’s essential drugs
list. (10, 11)

National procedure
The Nationalized procedure is one which allowsapplicants to obtain a marketing authorization in one member state only. (12, 13)

Mutual recognition procedure

The Mutual Recognition procedure allows applicants to obtain a marketing authorization in the member states (Concerned
Member State) other than the member state (Reference Member State) where the drug is previously approved. (15) Registration of
pharmaceutical drug products in emerging market is maximum worrying task. Although the requirements are harmonized in regulated
international locations by way of CTD (Common technical document) submitting, yet others have considerable diversity in
necessities. International conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
(ICH) has brought regulatory authorities and pharmaceutical industries of US, Japan and Europe collectively for various factors of
drug registration. But there is no such harmonized guideline for rising marketplace besides Association of Southeast Asian Nations
(ASEAN) and Gulf Co-operation Council (GCC) where harmonization exists in clusters with their mutual situation. Quality, Safety
and Efficacy information has significance importance in dossier registration. Pharmaceutical Industries has to conform with regulatory
requirement in Emerging market and for betterment of public Health and protection. 15

Regulation for filing Drug Product in Australia

Table 2: Registration process regulatory phases for NDA Approval Process (16)

Phases Regulatory requirements

Pre –  Applicants who have lodged complete PPFs willreceive Planning letter outlining:
submission -submission milestones
phase -any specific conditions for dossier logging.
-feedback from TGA on justification or other aspectsaffecting application.
 Applicant must certify that all information has beenpresented at the time of dossier logging.
Submission  TGA will process and consider submission dossier against regulatory requirements. Application not provided in
accordance with regulatory requirements will be considered not effective and not accepted for evaluation.

RESULT AND DISCUSSION

Drug approval process is generally composed of 2 steps: Clinical Trial Application and Application for Marketing
Authorization of drug to the Regulatory Authority. Information regarding Quality, Safety and Efficacy of the drug is almost similar in
all countries which is to be submitted to Regulatory Authority. But apart from this information, registration time, registration fees,
and clinical trial review process is different. ICH has taken many steps for Harmonisation. ICH developed CTD guidelines for US,
EU. This will minimize the duplication of work which is tobe carried out in Research and Development of the new drug.
The primary aim of regulation of drug products in Australia, US and Europe is regarding the public health. There are various
regulations for the development of the drug, its manufacture, trial and testing, so that they are safe for human use.

Conflict of Interest
The authors declare that there is no conflict of interest regarding the publication of this article.

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