1.What is Regulatory Affairs?

Ans-Regulatory Affairs in a Pharmaceutical industry, is a profession which acts as the

interface between the pharmaceutical industry and Drug Regulatory authorities across
the world. It is mainly involved in the registration of the drug products in respective
countries prior to their marketing.

2.What are the goals of Regulatory Affairs Professionals?

Ans-

 Protection of human health

 Ensuring safety, efficacy and quality of drugs

 Ensuring appropriateness and accuracy of product information

3.What are the Roles of Regulatory Affairs professionals?

Ans-

 Act as a liaison with regulatory agencies

 Preparation of organized and scientifically valid NDA, ANDA,INDA ,MAA,DMF

submissions

 Ensure adherence and compliance with all the applicable cGMP, ICH, GCP, GLP
guidelines, regulations and laws

 Providing expertise and regulatory intelligence in translating regulatory

requirements into practical workable plans

 Advising the companies on regulatory aspects and climate that would affect
their proposed activities

 Apart from the above main roles, there are various other roles which Regulatory
Affairs professionals play.

4.What is an Investigational New Drug (IND) application?

Ans- It is an application which is filed with FDA to get approval for legally testing an
experimental drug on human subjects in the USA

5.What is a New Drug Application?

Ans- The NDA is the vehicle through which drug sponsors formally propose that the
FDA approve a new pharmaceutical for sale and marketing in the U.S. The data
gathered during the animal studies and human clinical trials of an Investigational new
drug become part of the NDA
In simple words, “It is an application which is filed with FDA to market a new
Pharmaceutical for sale in USA”

6.What is an Abbreviated New Drug Application (ANDA)?

Ans- It is an application filed with FDA, for a U.S. generic drug approval for an existing
licensed medication or approved drug.
In simple words, “It is an application for the approval of Generic Drugs “

7.What is a Generic Drug Product?

Ans- A generic drug product is the one that is comparable to an innovator drug
product in dosage form, strength, route of administration, quality, performance
characteristics and intended use.

8.What is a DMF?
Ans- A Drug Master File (DMF) is a submission to the Food and Drug Administration
(FDA) that may be used to provide confidential detailed information about facilities,
processes, or articles used in the manufacturing, processing, packaging, and storing of
one or more human drugs.
Important facts regarding DMFs

 It is submitted to FDA to provide confidential information

 Its submission is not required by law or regulations
 It is neither approved nor disapproved
 It is filed with FDA to support NDA, IND, ANDA another DMF or amendments
and supplements to any of these
 It is provided for in the 21 CFR (Code of Federal Regulations) 314. 420
 It is not required when applicant references its own information
9.What are the types of DMF’s?
Ans-
Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (No longer
accepted by FDA)
Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their
Preparation, or Drug Product
Type III: Packaging Material
Type IV : Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Type V: FDA Accepted Reference Information (FDA discourages its use)

10.What is a 505 (b)(2) application ?

Ans- 505 (b)(2) application is a type of NDA for which one or more investigations relied
on by applicant for approval were not conducted by/for applicant and for which
applicant has not obtained a right of reference.

11.What kind of application can be submitted as a 505(b)(2) application?

Ans-

 New chemical entity (NCE)/new molecular entity (NME)

 Changes to previously approved drugs

12. What are the examples of changes to approved drug products for which
505(b)(2) application should be submitted ?
Ans-

 Change in dosage form.

 Change in strength

 Change in route of administration

 Substitution of an active ingredient in a formulation product

 Change in formulation

 Change in dosing regimen

 Change in active ingredient

 New combination Product

 New indication

 Change from prescription indication to OTC indication

  Naturally derived or recombinant active ingredient
 Bioinequivalence

13.What are the chemical classification codes for NDA?

Ans-
Number Meaning
1 New molecular entity (NME)
2 New ester, new salt, or other noncovalent
derivative
3 New formulation
4 New combination
5 New manufacturer
6 New indication
7 Drug already marketed, but without an approved
NDA
8 OTC (over-the-counter) switch

14.What are the differences between NDA and 505 (b)(2) application ?
Ans-
S.No. New Drug Application (NDA) 505 (b)(2) Application
1. All investigations relied on by applicant One or more investigation relied on by applicant
for approval were conducted by/for for approval were not conducted by/for
applicant and for which applicant has applicant and for which applicant has not
right of reference obtained a right of reference

2. Generally, filed for newly invented Generally, filed for new dosage form,
pharmaceuticals. new route of administration, new
indication etc for all already approved
pharmaceutical.

Note: 505 (b)(2) application is a type of NDA.

15.What is a Marketing Authorization Application?

Ans- It is an application filed with the relevant authority in the Europe (typically, the
UK's MHRA or the EMA’s Committee for Medicinal Products for Human Use (CHMP))
to market a drug or medicine.
As per UK’s MHRA-
Applications for new active substances are described as 'full applications'.
Applications for medicines containing existing active substances are described as
'abbreviated’ or ‘abridged applications’.

16.What is an ASMF?
Ans-Active substance master file is a submission which is made to EMA, MHRA or any
other Drug Regulatory Authority in Europe to provide confidential intellectual property
or 'know-how' of the manufacturer of the active substance.
In simple words, “It is a submission made to European Drug regulatory agencies on
the confidential information of Active Substance or Active pharmaceutical Ingredient
(API)”.

17.What are the types of active substances for which ASMFs are submitted?
Ans-

 New active substances

 Existing active substances not included in the European Pharmacopoeia (Ph.

Eur.) or the pharmacopoeia of an EU Member State

 Pharmacopeial active substances included in the Ph. Eur. or in the

pharmacopoeia of an EU Member State

18.What is the difference between DMF and ASMF (with respect to submission)?
Ans-ASMF is submitted as Applicant’s Part (Open Part) and Restricted Part (Closed
Part)
There isn’t any differentiation of DMF’s into parts

19.What is ICH?
Ans-International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH): is a project that brings together
the regulatory authorities of Europe, Japan and the United States and experts from
the pharmaceutical industry in the three regions to discuss scientific and technical
aspects of pharmaceutical product registration.

20.What is CTD?
Ans-The Common Technical Document (CTD) is a set of specification for application
dossier, for the registration of Medicines and designed to be used
across Europe, Japan and the United States.Quality, Safety and Efficacy information is
assembled in a common format through CTD .The CTD is maintained by
the International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
CTD format for submission of drug registration applications/dossiers is widely
accepted by regulatory authorities of other countries too like Canada, Australia etc.

21.What are the ICH guidelines to be referred for preparation of registration

dossiers/applications of medicines (With respect to format and contents in each
module)?
Ans-
M4 Guideline
M4Q Guideline
M4S Guideline
M4E Guideline

22.What are the modules in CTD?

Ans-
The Common Technical Document is divided into five modules:
Module 1. Administrative information and prescribing information
Module 2. Common Technical Document summaries (Overview and summary of
modules 3 to 5)
Module 3. Quality
Module 4. Nonclinical Study Reports (toxicology studies)
Module 5. Clinical Study Reports (clinical studies)

22.What is Orange Book?

Ans-

 It is the commonly used name for the book “Approved Drug Products with
Therapeutic Equivalence Evaluations”, which is published by USFDA.

 It contains the list of drug products, approved on the basis of safety and
effectiveness by the Food and Drug Administration (FDA) under the Federal
Food, Drug, and Cosmetic Act.

23.What is Hatch-Waxman act?

Ans-It is the popular name for Drug Price Competition and Patent Term
Restoration Act, 1984. It is considered as the landmark legislation which established
the modern system of generic drugs in USA. Hatch-Waxman amendment of the federal
food, drug and cosmetics act established the process by which, would be marketers of
generic drugs can file Abbreviated New Drug Application (ANDA) to seek FDA approval
of generic drugs. Paragraph IV of the act, allows 180 day exclusivity to companies that
are the "first-to-file" an ANDA against holders of patents for branded counterparts.
In simple words “Hatch-Waxman act is the amendment to Federal, Food, Drug and
Cosmetics act which established the modern system of approval of generics ”

24.What are the patent certifications under Hatch-Waxman act?

Ans-As per the Hatch and Waxman act, generic drug and 505 (b) (2) applicants should
include certifications in their applications for each patent listed in the “Orange Book”
for the innovator drug. This certification must state one of the following:
(I) that the required patent information relating to such patent has not been filed (Para
I certification);
(II) that such patent has expired (Para II certification);
(III) that the patent will expire on a particular date (Para III certification); or
(IV) that such patent is invalid or will not be infringed by the drug, for which approval
is being sought(Para IV certification).
A certification under paragraph I or II permits the ANDA to be approved immediately,
if it is otherwise eligible. A certification under paragraph III indicates that the ANDA
may be approved when the patent expires.

25.What is meant by 180 day exclusivity?

Ans-The Hatch-Waxman Amendments provide an incentive of 180 days of market
exclusivity to the “first” generic applicant who challenges a listed patent by filing a
paragraph IV certification and thereby runs the risk of having to defend a patent
infringement suit.
180 Day Exclusivity could be granted to more than one applicant. The recent example
is- 180 day exclusivity was granted to Ranbaxy and Watson Laboratories for marketing
generic version of Lipitor ( Atorvastatin calcium).

26.What are the procedures for Approval of Drug in EU?

Centralised Procedure (CP)
Decentralised Procedure (DCP)
Mutual Recognition Procedure (MRP)
National Procedure (NP)

27.What is the Full form of abbreviation, CEP?

Certificate of Suitability to the monographs of the European Pharmacopoeia
(or) Certificate of suitability of monographs of the European Pharmacopoeia (or)
Certification of suitability of European Pharmacopoeia monographs
It is also informally referred to as Certificate of Suitability (COS)

28.What is a CEP?
It is the certificate which is issued by Certification of Substances Division of European
Directorate for the Quality of Medicines (EDQM), when the manufacturer of a
substance provides proof that the quality of the substance is suitably controlled by the
relevant monographs of the European Pharmacopoeia.

29.What are the recently approved new Drugs by FDA (Under NDA Chemical
Type 1)? (As on 14th March, 2012)
Ans-
S.NO. NDA # NAME OF NAME OF ACTIVE COMPANY
DRUG INGREDIENT
1 203188 KALYDECO IVACAFTOR VERTEX PHARMS
2 203388 ERIVEDGE VISMODEGIB GENENTECH
3 202324 INLYTA AXITINIB PFIZER
4 202833 PICATO INGENOL MEBUTATE LEO PHARMA AS
5 202514 ZIOPTAN TAFLUPROST MERCK SHARP
DOHME
6 021746 SURFAXIN LUCINACTANT DISCOVERY
LABORATORIES INC

30.Full forms of some of the Abbreviations related to Regulatory Affairs-

S.No. Abbreviation Full Form
1 NDA New Drug Application
2 ANDA Abbreviated New Drug application
3 IND Investigational New Drug Application
 4 DMF Drug Master file
5 ASMF Active Substance Master File
6 MAA Marketing Authorisation Application
7 CEP Certificate of Suitability to the monographs of the
European Pharmacopoeia
8 ICH The International Conference on Harmonisation of
technical requirements for registration of Pharmaceuticals
for human use.
9 CTD Common technical document for the registration of
pharmaceuticals for human use.
10 AP Applicant’s Part
11 RP Restricted Part
12 OP Open Part
13 CP Closed Part
14 NME New Molecular Entity
15 NCE New Chemical Entity
16 SmPC Summary of Product Characteristics
17 PL Packaging Leaflet
18 RMS Reference Member State
19 CMS Concerned Member State
20 CHMP The Committee for Medicinal Products for Human Use
21 CPMP Committee for Proprietary Medicinal Products
22 CVMP Committee For Medicinal Products For Veterinary Use
23 SUPAC Scale-up and post approval changes
24 BACPAC Bulk Active Chemicals Post approval Changes
25 cGMP Current good Manufacturing Practice
26 GCP Good clinical Practice
27 GLP Good Laboratory Practice

31.Well known Drug Regulatory Agencies across the world-

S.No. Country /Region Regulatory Agency
 1 United States of United States Food and Drug Administration
America (USFDA)
2 United Kingdom Medicines and Healthcare products Regulatory
Agency (MHRA)
3 European Union European Medicines Agency (EMA)
4 European Union European Directorate for the Quality of Medicines
(EDQM)
5 Australia Therapeutic Goods Administration (TGA)
6 Canada Therapeutic Products Directorate (TPD) in Health
Product and food branch (HPFB) of Health Canada
(HC)
7 Japan Pharmaceutical and Medical Devices Agency
(PMDA)
8 France Agence Francaise de Securite Sanitaire des Produits
de Sante (AFSSAPS)
Translated into English as- French Agency for the
Safety of Health Products
9 Germany Bundesinstitut für Arzneimittel und
Medizinprodukte, (BfArM)
Tanslated into English as- Federal Institute for
Drugs and Medical Devices
10 Brazil Agência Nacional de Vigilância Sanitária (ANVISA)
Tanslated into English as- The National Health
Surveillance Agency
11 India Drugs Controller General of India (DCGI) who heads
Central Drugs Standard Control Organisation
(CDSCO)
12 Switzerland Swiss Agency for Therapeutic Products
(SWISSMEDIC)
14 Singapore Health Sciences Authority (HSA)
15 New Zealand New Zealand Medicines and Medical Devices Safety
Authority (MEDSAFE)

Effective Dossier Management in Regulatory Affairs

Importance of effective dossier management-
  The registration dossier for medicines is an important document which is submitted for
review to regulatory agencies by pharma companies for approval to market their
medicines.

 Utmost care should be taken during its compilation and filing as it plays a direct role
in earliest possible availability of medicines in the market which in turn translates into
business for the company.

 Of course, regulatory affairs professionals need to ensure the safety, quality and
efficacy of the medicines for which they are filing registration dossier.

Note : The dossiers could be anything among DMF, ASMF, ANDA, NDA or MAA.

From my experience I could possibly think of 3 important aspects which play an important role
in effective dossier management-

1. Planning aspects
2. Formatting and compilation aspects
3. Review aspects

1. Planning aspects-

 Deadline-It is important to know the deadline for filing the dossier and action plan
should be prepared so as to meet the deadline.

 Understanding the registration requirements of respective agencies- Although

most of the regulatory agencies accept the CTD format for registration dossier, the
requirements for approving marketing applications may vary for individual agencies.
For example- USFDA requires Batch Manufacturing Records to be provided, while it
is not necessary for approval by European regulatory agencies. Hence it is necessary to
completely read and understand the guidance document of each regulatory agency
before going ahead with filing registration dossier with them.
  Requirements Listing- Listing down all the requirements for preparing the registration
dossier, for example in the preparation of section 3.2.S.1 of a DMF I need to have all
the information on nomenclature, structure and general properties (like pH, Pka,
solubility, partition coefficient, stereochemistry etc ) of drug substance. Similarly
Listing down all the requirements for preparation of all the modules and their respective
sections is an important aspect.

 Sending the requirements list to respective departments-Preparing an individual

requirement list and sending them to each respective department. For example I need
to have all the information regarding the general properties, synthetic scheme,
manufacturing process development of drug from R & D department and finalised
specification & test procedures, Batch manufacturing sheets from Quality assurance
department.

2. Formatting and Compilation Aspects-

Format-

As per the ICH's M4 guideline the following are recommended-

 The display of information should be unambiguous and transparent, in order to facilitate

the review of the basic data and to help a reviewer become quickly oriented to the
application contents.

 Text and tables should be prepared using margins that allow the document to be printed
on both A4 and 8.5 x 11” paper (For Europe and Japan regions A4 paper is
recommended and 8.5 x 11” paper for USA).

 Times New Roman, 12-point font is recommended for narrative text.

 The left-hand margin should be sufficiently large that information is not obscured by
the method of binding.

 Font sizes for text and tables should be of a style and size that are large enough to be
easily legible, even after photocopying.

 Every page should be numbered, according to the granularity document (refer pages 6
to 14 of M4 guideline).

 Acronyms and abbreviations should be defined the first time they are used in each
module.

 References should be cited in accordance with the current edition of the Uniform
Requirements for Manuscripts Submitted to Biomedical Journals, International
Committee of Medical Journal Editors (ICMJE).

 All pages of a document should include a unique header or footer that briefly identifies
its subject matter.
Note: For any person who is new/relatively new to the field of RA it is important to read and
understand CTD guidelines of ICH (M4, M4Q,M4S, M4E) before starting to compile any
dossier. (Refer the post CTD in my blog)

Compilation-

The following compilation aspects are important-

 The information should be specific, clear, precise and accurate.

 Typographical and grammatical errors should be avoided.

 The information should be arranged in a sequential order in computer. Each module

could have a separate folder and in turn each section of a module could have a separate
folder. This kind of orderly arrangement will help in easy access of information and
help in taking printouts of finalized copy conveniently.

 The line spacing should be preferably single.

 All the documents received from other departments should be cross-checked so as to

ensure that they are free from errors.

 Ensuring the specifications & test procedures are designed in accordance with ICH
guidelines Q3A, Q3B, Q3C, Q6A and Q6B. Stability Protocols are designed as per ICH
guidelines Q1A through Q1E . Similarly ensuring that various documents are designed
as per ICH guidelines. This can be ensured during drafting stages of preparation of
various documents.

 After the finalized soft copy is ready, printouts should be taken using a good quality
printer and arranged sequentially in a module and section wise manner.

 As per the note given in the website of EMA-"All Microsoft Office documents
submitted to the European Medicines Agency must be in a format compatible with MS
Office 2003. Office 2007 and Office 2010 formats cannot currently be accepted".

3.Review Aspects

 .Every human being is prone to make mistakes; hence it is important to re check the
information in the dossier before filing it with regulatory agencies.

 It is also important that a dossier meant to be filed with a regulatory agency should be
cross verified by a person other than the one who has complied the dossier.

 It is very useful to have a check list so as to ensure that all the required information is
present in the dossier before submission to regulatory agency.

 The USFDA has a check list which is very useful while filing an ANDA- ANDA
checklist
  The module 1 of CTD in most of the cases is completely different for various agencies
hence care should be taken in compiling this section.

Avoiding Deficiencies-
You can learn without necessarily making mistakes. EDQM has compiled a list of top 10
deficiencies of CEP dossier which will go a long way in preventing you from making the same
mistakes.

Key software skills for effective dossier management-

 Proficiency in MS office (Yes, I know that most of you are proficient! ).

 Proficiency in Adobe Acrobat tools. (Especially useful in preparing NeeS dossier and
eCTD ).

 Proficiency in ISIS draw or Chem sketch softwares, which are useful in drawing
chemical structures.

 Since we generally receive number of mails on a daily basis, we could sort the emails
by using labels based on the sources. This will make your job easy while accessing
mails.

 eCTD is mandatory for the centralised procedures in Europe and it could be made
mandatory for the other procedures as well in the future. Hence it is important to
undergo training in the use of eCTD software.(My fellow Indian countrymen, let me
know if there are any institutes which are offering training in the use of eCTD software
back here in India)