Dhruvi et al.

International Journal of Drug Regulatory Affairs; 2017, 5(2), 1-12 ISSN: 2321 - 6794

PREPARATION AND REVIEW OF CHEMISTRY, MANUFACTURING AND CONTROL

(CMC) SECTIONS OF CTD DOSSIER FOR MARKETING AUTHORIZATION
Available online at www.ijdra.com
REVIEW ARTICLE
1
Dhruvi H. Patel, 2Badjatya Jitendra Kumar*, 1Patel Amit A.
1
Ramanbhai Patel College of Pharmacy, CHARUSAT Campus, Changa- 388 001, Gujarat, India.
2
Umedica Laboratories Pvt. Ltd., Vapi, Gujarat, India.
*Corresponding Author’s E-mail: jeetbadjatya@gmail.com
DOI: https://doi.org/10.22270/ijdra.v5i2.196

ABSTRACT

The present article summarizes & simplify the marketing application requirements i.e. the critical aspects of
marketing application in different CTD using countries, Process to prepare and review the requirements for CMC
section (Chemistry manufacturing & Control) for filing an application in regulated market. Study shows the
compilation of dossier as per CTD format with minimum errors during filing. The focus is on the application filing &
Query part that may come after submission & during approval process. So one has to focus on the requirements of
dossiers with minimal queries & study the probable queries that may arise after filing an application to regulated
countries. Once approved, the applicant can market the safe, effective, stable & quality generic drug product with low
cost to the public. The complete marketing application is based as per CTD format gives understanding of critical
aspects of Marketing Application and better understanding of dossier filing.
Keywords: CTD, CMC, Module, ICH, Dossier, Active Pharmaceutical Ingredients (API), Certificate of Analysis
(COA).

The full form of CTD is Common Technical

INTRODUCTION (1)
Document (CTD). It is organized into five
CTD Triangle: CTD triangle is set of modules:
documents contain the information about
Module 1: Administrative section (not a part of
product’s manufacturer detail, known as
administrative information, product’s quality CTD)
details in brief, Non-clinical and clinical study Module 2: Quality Overall Summaries
reports and summary of all this data which are
submitted to regulatory agency by applicant for Module 3: Quality
manufacturing, marketing or sell in the
respective country. Module 4: Non-Clinical Study reports
Module 5: Clinical Study reports
This CTD format mainly used for the
registration of pharmaceutical quality product in
various ICH harmonized country like USA,
Europe and Japan. This CTD documents are
submitted to the regulatory agency of this
country as per their countries guideline. In this
CTD format main focus is to harmonizing the
quality information mainly includes Chemistry
Manufacturing and Control (CMC) which is
submitted in an application format.
Figure 1: CTD Triangle

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Dhruvi et al. International Journal of Drug Regulatory Affairs; 2017, 5(2), 1-12 ISSN: 2321 - 6794

Chemistry Manufacturing and Control  The chemistry, manufacturing and controls

(CMC) (2, 3) (CMC) section is a very important part of
any clinical trial or marketing application.
CMC information in dossier is detailed and an Drugs can be denied marketing approval if
important section which support clinical trial as the quality of the product and the
well as marketing applications. This section manufacturing process cannot be shown to
must update during the drug development and be of a sufficiently high standard to satisfy
study. regulators.
C: Chemistry means Composition of drug  The ICH guideline Q1A(R2) (Stability
product Testing of New Drug Substances and
Products) defines the stability data package
M: Manufacturing means how we make the required for new drug substances and
product/ formulation products submitted for approval in each of
the major regions that accept the ICH
C: Controls means ensures whether products guidelines (i.e., US, Japan and EU).
meet their predetermined specification/quality
attribute. DOSSIER TECHNICAL SECTION
COMPILATION
ICH guidelines gives general idea about CMC
but there lack of exact content of guidance One has to save time during product approval;
documents. process during filing an application & to get rid
from unnecessary queries that may lengthen the
Content depends upon the type of product like if approval process Therefore one has to focus on
it pharmaceutical, biological, Biosimilars, the probable queries that may arise after
generics or vaccines. submission of marketing application. Once
approved, the applicant may manufacture and
Details of the sections depend upon the type of
market the generic drug product to provide safe,
the product and countries specific requirements.
effective and stable & quality product with low
If it is Pharma product than it contains least
cost to the public. The queries of CMC section
content and it is well described/ characterized.
compiled in CTD format as per ICH guideline:
In ICH all guidance documents are described in “The Common Technical Document for the
detail about CMC. The required format, data Registration of Pharmaceuticals for Human Use
and content are also given in ICH. [M4Q (R1)] which gives good understanding of
critical aspects of marketing application in ICH
Importance of CMC Section in CTD Dossier harmonized countries like US, Europe and Japan
(2, 3) and their market requirements.
 For any marketing application or clinical MODULE 3: QUALITY (4, 5)
trials CMC (chemistry, manufacturing and
controls) section is a very important and 3.2 Body of Data
detailed section.
3.2. S DRUG SUBSTANCE
 If the manufacturing process cannot be
shown to its highest quality standard and do 3.2. S.1 General Information
not satisfied the regulators need as well as
product have not their quality standard as 3.2. S.1.1: Nomenclature
mentioned in Pharmacopoeia than it might
be chance to drug may lost the marketing Section Queries:
approval. 1. USAN, BAN, IUPAC, names, CAS not
 So it is important to show the standard provided
quality process and parameter of drug
manufacturing details and other parameter 3.2. S.1.2: Structure
cover in module 3 Quality contain
Chemistry, manufacturing and Control. Section Queries:

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Dhruvi et al. International Journal of Drug Regulatory Affairs; 2017, 5(2), 1-12 ISSN: 2321 - 6794

1. Stereochemistry, Isomerism structure and 4. Intermediates formed during the reaction

discussion on the drug substance used in (synthesis), starting materials, solvents and
formulation is absent. reagents specifications are confusing and
incomplete.
3.2. S.1.3: General Properties
5. By two different route of synthesis the final
Section Queries: product is manufactured. Though no
consideration has been given to each route
1. In the presentation, nature of drug is not of the impurity profiling of the drug product.
discussed. Drug known to be a polymorphic 6. In the synthesis of the Drug substance and
in nature. product most unsafe chemicals Cyanide is
2. Polymorphism and chirality is not used. On the other hand route of synthesis
mentioned adequately. may be changed but the same requires
3. The physical constants such as solubility in substitution with another secure
organic solvent, water, buffers at different chemical/reagent.
pH values are poorly described. 7. The synthesis of the API involves many
4. Existence/absence of polymorphism and stages. But no one is mentioned about
chirality is not discussed. residual impurities come from starting
5. Particle size distribution, Hygroscopicity, materials and also from intermediates which
granularity, flowability etc. not described in are formed during the synthesis reaction
detail. 8. The starting materials resource not
6. A description on solubility based on disclosed.
different pH buffers (pH 1.2, 4.6 & 6.8) not 9. The starting materials involve harmful and
provided. lethal reagents in route of synthesis.
7. pKa value not included in section.
3.2. S.2.3: Control of Materials
3.2. S.2: Manufacture
Section Queries:
3.2. S.2.1: Manufacturer(s)
1. The residual metals from the reaction
Section Queries: procedure are poorly addressed.
2. The raw materials, reagents, intermediates
1. Though Active Pharmaceutical Ingredients and solvents used in the process are not
(API) is manufactured from two different described properly for possible impurities.
manufacturers. Name and complete contact
details of each API-Vendor are not given. 3.2. S.2.4: Control of Critical Steps &
2. Good manufacturing practice (cGMP) Intermediates
certificate which given from an authorized
1. The Control of Materials not complemented
regulatory body is necessary to be submitted
by the supplier & the In-house Certificate of
for API manufacturer.
analysis.
3.2. S.2.2: Description of Manufacturing 2. Critical Steps not checked with the Process
Process & Process Controls Development report & are not co-related.
Further a proper justification should be in
Section Quarries: place for classifying them as Critical (this
1. In the API synthesis full details of the information must be present in the
reactions steps used is not described. The Development report)
API purification steps are not provided. The 3.2. S.2.5: Process Validation and/or
specifications of reagents, starting materials, Evaluation
intermediates, catalysts, and solvents used in
the reaction are not fully described. Section Queries:
2. In case of Advanced Intermediate the
Chemistry of the same not included. 1. During process validation three consecutive
3. Route of manufacturing, brief process and batches must be provided.
reaction scheme details are not given.

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Dhruvi et al. International Journal of Drug Regulatory Affairs; 2017, 5(2), 1-12 ISSN: 2321 - 6794

2. Three different batches are performed for acceptable one due to sufficient solubility to
stability study not performed on Process ensure optimal bioavailability. However, the
Validation. specification does not consider inclusion of
3. Process Validation Protocol (PVP) & Report polymorphic forms, as it has critical quality
has to be co-related with the Batch attributes to the finished product. It is
manufacturing Records & must be verified assumed that the FPP manufacturer should
for all in-process & critical parameters. have a protocol and mechanism of
Critical parameters should be captured in the verification to ensure the consistent supply
PVP & must be connected to the of the desired polymorphic form. However,
Development Report. nothing is said on this important issue either
4. In process validation three different batch on the pharmaceutical development data or
sizes are used as batch analysis. on the process validation. Provide the
precautions and testing procedures
3.2. S.2.6: Manufacturing Process
undertaken to confirm consistent the supply
Development
of the right polymorph. In addition, provide
Section Queries: the conditions that lead the interconversion
of the polymorphs. Furthermore, the
1. Particle size distributions, Hygroscopicity, precautions that is taken during the
granularity, flowability, etc. are not manufacture of the finished product to
described in brief. prevent interconversion among the
2. PDR (Pharmaceutical development reports) polymorphs at the FPP manufacturing
are not complete. conditions. (Wet granulation, drying,
3.2. S.3: Characterization blending and compression).
3.2. S.3.2: Impurities
3.2. S.3.1: Elucidation of Structure and other
Characteristics Section Queries:
Section Queries: 1. Apart from the normal Process impurities,
Residual Solvents & Degradation impurities,
1. Proper scientific information should be impurities due to the Starting material
provided for the Polymorphism & should be included in the write up.
Identification of Stereochemistry of the 2. The impurities must be also appropriately
Active Ingredient amongst other spectral captured in the Specification of the Final
studies. (For e.g. IR, UV, NMR, Mass, DSC, Product.
XRD etc.) 3. However toluene is used as solvent in the
2. The spectral data such as NMR, X-ray synthesis but not tested the same for
Diffraction, Elemental Analysis and IR as a presence of residual benzene.
means for evidence of chemical structure is 4. The product from each source impurity
missing. profiling is not given.
3. In the presentation nature of API is not 5. In the synthesis process residual solvent
discussed while drug known to be levels are exceeding the Pharmacopoeias
polymorphic in nature. limit.
4. Polymorphism and chirality are not properly 6. The lot number, source and purity of the
addressed. impurity standards are not described.
5. For Drug substance spectral graphs for UV 7. Potential impurities are not described in the
Spectra, NMR & IR studies performed are impurity profile.
unacceptable and interpretation of the 8. For the impurities measurement methods are
studies is inadequate. used are not qualified.
6. The API exhibits polymorphism which can 9. The Finished product manufacturer needs to
potentially affect the quality and efficacy of have a mechanism for controlling impurities,
the finished product. Based on the provided and residual solvents and should include in
information, the API has three polymorphic its own API specification. However, such
form of A, B &C type. Polymorph C is the information is not considered and provided
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Dhruvi et al. International Journal of Drug Regulatory Affairs; 2017, 5(2), 1-12 ISSN: 2321 - 6794

in the API part of the submitted dossier. This 7. Residual Solvents needs to be included.
may imply that you are directly accepting Benzene is class I solvent used in synthesis
the API manufacturer’s specification and of the drug products. These solvents limits
certificate of analysis (COA) without are not described.
verification. Please clarify and justify this
3.2. S.4.2: Analytical Procedures
issue against the guideline.
10. In the synthesis raw materials and Section Queries:
intermediates are used. Their specifications
of are not described. Although hazardous 1. Assay & Related substances will have to
reagents and inorganic toxic substances are have a Stability indicating method (although
used in the reaction but the same residual the compendia method may be titration/TLC
limits are not given. etc.)
11. Benzene is class I solvent used in the 2. The method reference (compendia/ in house)
synthesis of the drug substance and should be included in the specification page
products. The residual limits for class I of the DMF.
solvent are not described tested at any point. 3. In the product chiral impurities are present.
12. The source of raw materials is not disclosed. The part assay process is insufficient to
13. The unknown impurities present in the API control chiral impurities.
are more than ICH limits. 4. The Limit of Quantification (LOQ) and the
14. For certain basic substance where no limit of detection (LOD) are not provided
specific HPLC method for analysis of API for GC and HPLC methods used to control
basic in nature is available on specific residual solvents and impurities in the Drug
methods such as Non aqueous titration by substance.
Perchloric acid is permitted by FDA. 5. The HPLC method employed for assay of
However, in such cases the impurities must the impurities and API is similar. From
by analysed by HPLC/GC. method validation data it has been observed
15. All known impurities, Single unknown & that the method is inadequate for the assay
total impurities needs to control. of the impurities but appropriate for the
assay of drug substance.
3.2. S.4: Control of Drug Substance 6. The method used for the study of Drug
3.2. S.4.1: Specification substance is not specific. For the Analysis of
impurities specific method is used which are
Section Queries: not provided.
7. In-house method has been provided by
1. API specifications lack attributes additional Common Technical Documents holder by
to compendia monograph, e.g. residual his own for the study of impurities and API
solvents, particle size distribution, chirality, without any validation information.
polymorphism, crystal structure. 8. For definite isomeric/chiral impurities the
2. The quality of the APIs meet only the starting source/materials are not studied
requirements of specific monographs but which can be accepted ahead.
does not meet to specifications described in 9. The In-house analytical method validation
the general monographs of a pharmacopoeia. reports not described in brief. For final
3. The specific test for the control chirality of purification solvent and water used, the
the drug substance is not provided. quality of the same is not described.
4. The quality of the APIs meets only the
requirements of specific monographs but 3.2. S.4.3: Validation of Analytical
does not meet to specifications described in Procedures
the general monographs of a pharmacopoeia.
Section Queries:
5. An XRD test is a must should the molecule
exhibit a polymorph. 1. Definite validated GLC/HPLC methods for
6. Catalyst if any used in the synthesis of the qualify the impurities are unavailable. Using
API may be controlled (not necessary if qualitative TLC test impurity profiling is
absence in 3 batches shown) performed
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Dhruvi et al. International Journal of Drug Regulatory Affairs; 2017, 5(2), 1-12 ISSN: 2321 - 6794

2. The In-house analytical method used for the 3.2. S.6: Container Closure System
drug product needs through validation. In
MOH laboratory the tests performed for Section Queries:
validation is indicated vague.
1. IR spectra of the Polybags needs to be
3. For determination of residual solvents by
submitted. (Identification for the material of
GC you were compulsory to modify the
construction)
validation, which should have included
2. For immediate container of the API product
intermediate precision, robustness and inter
polymer is used need to be tested, identified
laboratory validation.
and characterized as per specifications given
4. The method validated should be the same as
in Pharmacopeia’s General Monographs.
that of the final method adopted to test the
Drug substance. 3.2. S.7: Stability
5. For determination of residual solvents by
GC you were compulsory to modify the 3.2. S.7.1: Stability Summary and Conclusions
validation, which should have included 3.2. S.7.2: Post-approval Stability Protocol
intermediate precision, robustness and inter and Stability Commitment
laboratory validation.
6. Typical chromatograms may be provided for 3.2. S.7.3: Stability Data
a particular batch of the API.
Section Queries:
3.2. S.4.4: Batch Analyses
1. The actual studies for stability are not
Section Queries: provided. Data is provided from literature of
1. For 3 initial batches of API production the forced degradation study.
test result provided are in abbreviated form. 2. For stability studies the stability indicating
2. Significant differences between the API method has not been used.
manufacturers and FPP manufacturer’s 3. In Stability summary does not concluded
batch study/analysis were noted for acetone, about primary packaging material, proposed
isopropyl alcohol and methanol storage conditions.
3. The COA’s (certificate of analysis) should 4. For ongoing stability study: Post Approval
have the batch size mentioned among other stability commitment not provided.
typical details. 5. Check the Stability specification against the
test protocol (Stability protocol), the
3.2. S.4.5: Justification of Specification Stability condition & Stability time points.
Check parameters like Polymorphism etc.
Section Queries: 6. Microbial Attributes test not provided and/or
1. Justification for use of highly hydrates form not provided at Initial and final stage in
of API used in the product is not provided. stability data.
3.2. P DRUG PRODUCT
3.2. S.5: Reference Standards or Materials
3.2. P.1 Description and Composition of the
Section Queries:
Drug Product
1. Certificate of Analysis (COA) for working/
1. API Overages qty. not mentioned in
secondary standards are not provided by
formula.
manufacturer.
2. Formula of API assay potency calculation
2. Reference standards/materials must be well
details not provided.
characterized.
3. Functions of material details not provided.
3. The C of A’s of all working standards are
4. Information on the quantity dispensed with
provided without typical chromatograms. In
respect to API taking into the Assay (on as is
case of Reference standards used then the
basis or anhydrous basis). Weight
proper Lot number needs to be given.
adjustment with respect to the quantity of

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Dhruvi et al. International Journal of Drug Regulatory Affairs; 2017, 5(2), 1-12 ISSN: 2321 - 6794

diluent needs to be provided as per the 3.2. P.2.2: Drug Product

calculations of the BMR.
5. Solvents not present in the product should be 3.2. P.2.2.1 Formulation Development
clearly mentioned.
Section Queries:
6. The Qualitative & Quantitative certificate of
a colorant needs to be appropriately 1. The final product is manufactured using
provided. critical raw materials from two different
3.2. P.2: Pharmaceutical Development suppliers. However, no special attention has
been given to differences in quality of the
3.2. P.2.1 Components of the Drug Product end product.
2. The development report should be prepared
3.2. P.2.1.1 Drug Substance by taking into consideration QbD concept.
3. The process control details such as moisture
Section Queries:
(range), blend uniformity, bulk and tapped
1. No discussion on formulation with respect to densities and particle size distribution are
reference product. No mention of BA not provided.
study/clinical studies or study batch details. 4. Discriminatory dissolution methods will
2. Active and process detail discussed. Each have to be developed, the influence of
Excipient discussed. But for compatibility particle size will have to be studied.
conclusion provided but method and no
actual data has been provided. Documents 3.2. P.2.2.2 Overages
(PDR) needs to be developed accordingly. 1. Formula of API assay potency calculation
3. Polymorphism, Stereochemistry, Isomerism details not provided.
studies and discussion on the drug substance
used in formulation is absent. 3.2. P.2.2.3 Physicochemical & Biological
3.2. P.2.1.2 Excipients Properties

Section Queries: Section Queries:

1. Please clarify the need of the preservatives 1. Physicochemical parameters &

in this tablet dosage form and explain the Microbiological attributes not addressed
conditions of manufacture and overall properly.
relevant composition that let you use such 3.2. P.2.3: Manufacturing Process
preservatives. Your justification should be Development
supported with relevant comparator product
composition or specification and Section Queries:
pharmaceutical guidelines/Excipient books.
In addition, the amount used has to be 1. The process control information such as,
justified if the additions of them are weight variation, average weight hardness,
scientifically justifiable and acceptable. friability, thickness and disintegration time
2. Although you have used preservatives, are not provided for tablet dosage form.
microbial limit tests and such information 2. The manufacturing development should be a
are not provided in the pharmaceutical reproducible during the actual batch
development data or later in the commercial manufactured. The In-process checks & the
scale batch manufacturing specifications. intermediates defined in the development
Clarify this. report needs to be captured aptly during the
3. PDR (Pharmaceutical development reports) actual manufacturing (3.2.P.3)
are not complete. 3.2. P.2.4: Container Closure System
4. A quantitative estimation of excipients may
be necessary to prove equivalence b/w the Section Queries:
Test & the innovator.

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1. Primary packaging material Certificate of 7. The information on some hazardous

Analysis (COA) & Standard Test Procedure materials like reagent and solvent is hidden.
(STP) are not given. 8. All excipient and raw materials not
2. Pack style and pack size discussion is not mentioned in batch formula.
provided. 9. Provide justification/declaration stating that
the submitted qualitative-quantitative
3.2. P.2.5: Microbiological Attributes
formula corresponds to the subject drug
Section Queries: product. Note that the reflected product
name in the submitted documents in product.
1. Microbial Contamination results are
3.2. P.3.3: Description of Manufacturing
missing.
2. Pathogen Count and Total Count not Process & Process Controls
provided. Section Queries:
3.2. P.2.6: Compatibility
1. The manufacturing process write up should
Section Queries: be generic in nature & should not stress on
the manufacturing operational parameters as
1. All Excipients are not used during the it may vary during actual manufacturing
compatibility study with API. process & this may lead to an unnecessary
variation post approval.
3.2. P.3: Manufacture
3.2. P.3.4. Control of Critical Steps and
3.2. P.3.1: Manufacturer(s) Intermediates
Section Queries: 1. The process control details such as average
1. Manufacturer complete address for weight, weight variation, hardness,
manufacturing plant & Head office with thickness, friability and disintegration are
contact of Quality person not mentioned. not provided for your tablet dosage form.
2. Critical parameters defined/captured in
3.2. P.3.2: Batch formula Process validation should always be
concordant with the Product development
Section Queries:
3.2. P.3.5: Process Validation / Evaluation
1. In batch formula some of the Excipients
used in the drug formulations is not Section Queries:
included.
2. The standard and quantity for some 1. Process validation report on first 3
Excipients not indicated in the unit and commercial batches is not provided.
batch formula. 2. The Prospective Process Validation on 3
3. The batch formula not mentioned for the initial batches has not been provided. The
exhibit as well as the proposed commercial retro prospective Process Validation data
batch. The manufacturing process & the in- submitted is inadequate to conclude that
process controls are to match with the your manufacturing process is valid.
Product development report. 3. A co-relation with the PVP & the PVR with
4. The composition and test methods for the the executed BMR needs to be properly
commercial colorant mixtures are used for done.
tablet coating are not described in details. 3.2. P.4: Control of Excipient
5. In drug formulation titanium dioxide is used
as Opacifier but mentioned in batch formula. 3.2. P.4.1: Specification
Also the complete composition of the
coating materials is not provided. Section Queries:
6. For film coating of product organic solvent
are used. It is not mentioned anywhere.

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1. Excipients are provided in In-house 2. In FP (Finished Product) specification

specification despite of that the same are microbial limit is not included.
present in Pharmacopoeia. 3. General Specifications provided for the drug
substances are totally ignored. While the
3.2. P.4.2: Analytical Procedures product is analyzed as per specifications
provided in British Pharmacopeia.
1. Excipients limits are not complying as per
4. The submitted finished product specification
the Pharmacopoeia monograph.
corresponds to the subject’s drug product.
3.2. P.4.3: Validation of Analytical Provide declaration and justification of the
Procedures statement.
5. Micro test is not mentioned anywhere.
1. Chromatography condition not as per 6. The assay limits at release should have been
Specification. revised to 95-105% wider limits for shelf
life could be applied.
2. Excipients specification provided as In- 7. No test for water as per ICH Q6A for oral
house but Analytical method validation not dosage form.
provided. 8. Besides again if the additions are acceptable,
3.2. P.4.4: Justification of Specifications the FPP specification need to include their
assay limits and acceptance criteria and
1. For In-house parameters justification of should also appear in the stability
specification not provided. specifications as one critical stability
indicating parameter.
3.2. P.4.5: Excipients of Human or Animal
origin 3.2. P.5.2: Analytical Procedures

1. For the sensitive Excipients e.g. Mg-stearate Section Queries:

TSE/BSE declaration is not provided. 1. The assay procedure is nonspecific. The
2. TSE/BSE aspects of raw materials are specifications for in-house product are not
totally ignored. clear and complete. The test for identity and
3. TSE/BSE Certificates are not provided as impurities are not described at all. It’s need
per AR No. used in the batches that are to be duly validated GC/HPLC based
required to be submitted in the marketing specific assay method.
application. 2. In Certificate of Analysis (COA) the
3.2. P.4.6 Novel Excipients quantitative values provide are below the
limit of Quantitation. (LOQ).
Section Queries: 3. Carcinogenic solvents like Methanol
Acetone and IPA have been used in
1. The Excipients used for manufacturing your
synthesis. However, these solvents are not
Tablet dosage form is Novel. The
analyzed for chance contamination of Class
manufacturers have not provided enough
I solvents from which they are prepared.
data on its source, synthesis, characterization
4. Details for the micro limit test are not given.
and safety.
5. Provide Certificate of Analysis (COA) of
3.2. P.5: Control of Drug Product finished product from the same batch of
representative sample.
3.2. P.5.1: Specification 6. Clarify why does the batch size reflected in
the Certificate of Analysis is different to
Section Queries: submitted Quantitative-Qualitative formula.
1. Make sure that the specification is 7. A check on the presence of Genotoxic
scientifically designed & the levels of impurities needs to be studied which may
impurities need to be justified as per ICH arise from within the Drug product.
depending on the daily dose of the drug. 8. Certificate of Analysis (COA) and other
Quality Control (QC) documents are not

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signed dated and certified by Quality 7. In batch analysis data the source, lot
Assurance (QA) department. number, and purity of the impurity standards
are not provided.
3.2. P.5.3: Validation of Analytical
8. Provide the test method detail for the
Procedures
impurities. Only limits for impurities are
Section Queries: provided.
9. In the synthesis the catalysts such as
1. The tests performed in MOH laboratory Palladium and Platinum are used of the
indicate that the method unclear. products. Specify the residual limits for the
2. Validation procedure is required for the in- same.
house analytical procedure provided for the 10. Please determine the residual impurity of the
product. same.
3. For impurities or microbiological test
validation test are required. 3.2. P.5.6: Justification of Specification
4. Method validation for Assay, Related Section Queries:
substances, Dissolution & Residual solvents
methods needs to be presented taking into 3.2. P.6: Reference Standards
account all the parameters defined as per
ICH. Section Queries:
5. Photostability & Forced Degradation Studies
1. Reference materials/standards are poorly
needs to be presented.
characterized.
3.2. P.5.4: Batch Analyses 2. Please provide the IR spectra. Dissolution
test should be provided.
1. Three Batches data not provided. 3. The qualification details should be clearly
stated in case a Working standard is
2. COA for drug product for all three batches
qualified (against a Reference standard).
& Raw data &/Chromatograms are missing.
3.2. P.7: Container Closure System
3.2. P.5.5: Characterization of Impurities
Section Queries:
Section Queries:
1. For the proposed blister pack the moisture
1. Potential impurities are not discussed. permeation data are not provided.
Methods used to assess impurities are not 2. For final packaging the extractable and
qualified. leachable study for the plastic containers and
2. Although inorganic toxic substances and stoppers used for the drug product
hazardous reagents are used in the process packaging is not provided.
but residual limits are not provided. 3. Labelling materials (actual/commercial
3. In the synthesis specifications of raw label)
materials and intermediates used are not It was noted that there’s a change in the
provided. blister design, as well as, inclusion of ADR
4. In the reaction process Excipients used Reporting Statement in the Unit Carton Box
which may carry reactive impurities such as and Package Insert, but no application for
Hydrogen peroxide (other oxidized species), change of product labelling (MiV-PA2).
formaldehyde and Formic Acid. Justification Company has to provide the requirements as
for the use of this Excipient is not provided. per ASEAN Variation Guideline for
5. Impurities in residual solvents (ICH Q3C) Pharmaceutical Products and pay the
and USP <467> are not adequately corresponding fee.
described. 4. The primary packaging specifications should
6. Genotoxic impurities needs to be studied have included an identification test for
which may arise from within the Drug aluminium and an IR test for the PVD
product. coating. Additionally, you were required to
provide an IR spectrum for PVC coating.

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Dhruvi et al. International Journal of Drug Regulatory Affairs; 2017, 5(2), 1-12 ISSN: 2321 - 6794

3.2. P.8: Stability “…in conversation with Speaker from the

Raaj GPRAC workshop (Badjatya JK:
3.2. P.8.1: Stability Summary and Conclusion Conversation with: Ms. Rajashri Ojha; 2012
Oct 26-27).”
3.2. P.8.2: Post approval Stability protocol
and stability Additional all Sections Queries (M1 to M5)
(6)
3.2. P.8.3: Stability Data
1. In the dossier Module IV and V, supportive
Section Queries: clinical and nonclinical full text articles are
not provided.
1. Do not consider zone-conditions for Real-
2. Literatures refer in Module IV and V is
time stability studies.
poorly summarized in Module II.
2. In stability report the packaging details are
Furthermore, the nonclinical and clinical
missing.
summaries do not match with the full text
3. The expiry date assigned to the product is
articles provided in Module IV and V.
not matching with the stability data
3. In Module IV and Module V full reference
provided.
particulars of literature and photocopies used
4. Provide justification/declaration stating that
are illegible and cannot read correctly.
the submitted long-term and accelerated
4. Files are bound properly.
stability studies correspond to the subject
5. Table of contents is not complete.
drug product.
6. In the dossier version number and date
5. In the drug product specification like release
assigned are not assigned.
and shelf life should be included.
7. Pagination of the submission is out of order.
Preservative content should be quantified up
8. Some of the documents provided in dossier
to shelf life.
such as method validation, stability studies
6. During stability study related substance and
report and process validation are not in
impurities are must be tested
English.
7. Company XYZ claim stating “Since the
9. Scoring and Engraving details for your
product is well established, accelerated
formulation/ preparation (e.g, tablet) is not
stability study is not required” is absolutely
provided.
unacceptable and the provided real time data
10. On the label the preservatives used in your
is not acceptable unless the above requested
injectable dosage forms are not declared.
quires are sufficiently justified and all the
11. Bio-waver for products of different strengths
necessary corrections have made. We advise
is poorly justified.
you to commence an accelerated and real
12. On the API (drug substance) section: API
time stability study according to our
overall information according to module III
guideline and provide us the information as
was expected from both the drug substance
soon as possible.
and FPP manufacturers. Especially, the open
8. Release and stability specifications are must
part of the drug master file should come
provided.
from the API supplier according to our
9. In stability summary does not include
guideline. Although you have submitted API
conclusions with respect to shelf-life and
information, it is not satisfactory and
storage conditions.
complete. Therefore, you are requested to
10. For ongoing stability study: Post Approval
provide each part of the API section
stability commitment not provided.
according the guideline.
11. For stability studies the stability indicating
13. Good manufacturing practice (cGMP)
method has not been used.
certificate for API manufacturer which given
12. For In-House product the Shelf life
from a recognized (authorized) body is
specifications are not clear and complete.
required to be submitted.
13. Provide justification/declaration stating that
14. Bioequivalence study with the appropriate
the submitted accelerated and long term
comparator product is not provided. As it is
stability studies correspond to the subject
known that the API is practically in water
drug product.
and there is also a huge concern on the
© 2017 IJDRA Publishing Group, All rights reserved Page 11
Dhruvi et al. International Journal of Drug Regulatory Affairs; 2017, 5(2), 1-12 ISSN: 2321 - 6794

polymorphic forms as described above, Article. We also thank to Dr. Jitendra Kumar
besides, on the basis of Biopharmaceutics Badjatya (Umedica Laboratories Pvt. Ltd.) and
classification system (BCS), it does not meet Dr. Amit A. Patel (Ramanbhai Patel College of
the requirement of biowaiver. Consequently, Pharmacy, CHARUSAT University), for their
your waiver request of in-vivo testing is not guidance & support in writing the article and for
acceptable. And so, you are kindly requested their support.
to provide the necessary information
according to our guideline. DISCLAIMER
15. Integrated form- Not provided in Re-
The views and opinions expressed in this article
application.
are those of the author and do not reflect or
16. In this dossier Finished product
represent the views of the company the author
specifications are provided for Batch No.
works for in any manner.
(ZY 601, ZY 602 & ZY 603), validation
done on batch No. (ZY 302, ZY 401 & ZY CONFLICT OF INTEREST
402) and stability data for batch no. (ZY 302
& ZY 201). The authors declare that there are no conflicts of
17. It was noted that there is a change in the interest.
blister design, as well as, inclusion of ADR
reporting statement in the Unit carton REFERENCE
labeling. Company to provide the 1. Guidance for Industry M4Q CTD [Internet]. US
requirements as per ASEAN variation Department of Health & Human Services, ICH;
guideline for Pharmaceutical products and August 2001 [Cited 2017 April 14]. Available from:
pay the corresponding fee. https://www.fda.gov/OHRMS/DOCKETS/98fr/02d-
0525gdl00001.PDF
CONCLUSION 2. Robinett RS Robin. Merck & Co., Inc, Merck.
[Internet]. 75th AMWA Conference; 2015 Oct
Marketing Application is an application for an 1[Cited 2017 April 11]. Available from:
approval for generic drug product. Application http://www.amwa.org/files/Events/AC2015/OS_Slide
s/OS11_CMC101.pdf
is submitted to ICH regions for marketing 3. Chemistry manufacturing and control requirements,
authorization, which provides for the review and [Internet]. MaRS; 2010 [Cited 2017 April 17].
ultimate approval of generic drug product. Once Available from:
approved, the applicant may manufacture and https://www.marsdd.com/wp-
market the generic drug product to provide safe, content/uploads/2012/09/CMC-Requirements. pdf
4. European medicine of Agency [Internet].
effective and stable drug product with low cost CPMP/ICH; 2003 July [Cited 2017 April 19].
effectiveness to public. Available from:
http://www.ema.europa.eu/docs/en_GB/document_lib
The present study is carried to find out the rary/Scientific_guideline/2009/09/WC500002725.pdf
probable queries that may arise while submitting 5. George Wade EMEA [Internet]. The Common
our marketing application to the agency. This Technical Documents-Quality (CTD-Q); 2008 Feb
article aim to focus on the Module 3 (CMC [Cited 2017 April 23]. Available from:
http://www.ema.europa.eu/docs/en_GB/document_lib
Section) queries. Reference for format is rary/Presentation/2009/10/WC500004211.pdf
brought from ICH guideline – Notice to 6. Mr. R.M. Gupta. [Internet]. Top 50 Deficiencies in
applicant. CTD Dossiers [Cited 2017 April 09]. Available
From:
The careful reviewing & compilation helps the http://www.perfectdossier.com/pdf/Top%2050%20D
Regulatory Affairs professional to minimise the eficiencies%20in%20CTD%20Dossiers.pdf
error/probable queries & gives good
understanding of critical aspects of marketing
application and better understanding of filing of
CMC section of the dossier.
ACKNOWLEDGEMENT
I take this opportunity to express my deep sense
of gratitude to IJDRA Journal for publishing my
© 2017 IJDRA Publishing Group, All rights reserved Page 12