Overview of Regulatory Affairs

1. Overview of
REGULATORY AFFAIRS
BY
CHANDRA MOHAN MADDALA

2. • INTRODUCTION
• WHAT IS RA
• WHY IS RA
• COMMON TECHNICAL DOCUMENT (CTD)
• USFDA FILING
• EUROPE FILINGS
• DIFFERENCES B/W USFDA & EU FILINGS

3. INTRODUCTION
Origin:
Regulation has stemmed from avoiding the repetition of disasters
 Diphtheria Epidemic - 1901
 Elixir sulfanilamide - 1937
 Thalidomide disaster - 1962
In the USA, this regulation is largely written directly into law and codified in Title 21 of the
Code of Federal Regulations

4. THALIDOMIDE DISASTER

5. THALIDOMIDE DISASTER

6. THALIDOMIDE DISASTER

7. WHAT IS RA?
• Regulatory Affairs also called Government Affairs
• 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.

8. WHAT IS RA?

9. WHAT IS RA?
• The main goals of a regulatory professional:
- Protection of human health
- Ensuring safety, efficacy and quality of drugs
- Ensuring accuracy of product information.

10. WHY IS RA?
• Regulatory affairs ensure that pharmaceutical products to meet legislative requirements.
• Key duties:
- Studying scientific and legal documents.
- Gathering, evaluating, organising, managing of submission documents and
- Collating information in a variety of formats.

11. COMMON TECHNICAL DOCUMENT (CTD)
• The registration documents that needs to be filed is in a format called CTD & more so
now as an electronic version that is called e-CTD. The content of the CTD/e-CTD is
the same.
• e-CTD is a software programmed based submission which is easier, faster &
convenient. Most of the agencies have made this format of submission compulsory
now.
• The purpose of this CTD is to provide a harmonised structure and format for new
product applications (marketing authorization).
• The modular framework of CTD is described in the ICH guidelines (ICH Topic M4).

12. CTD STRUCTURE
The CTD is organized into FIVE modules:
• Module 1: Administrative Information.
• Module 2: CTD Summaries
• Module 3: Quality
• Module 4: Nonclinical Study Reports
• Module 5: Clinical Study Reports

14. CTD STRUCTURE
Module 1: Administrative Information
• Table of contents of the submission including Module 1
• Documents specific to each region (for example, application forms, prescribing
information)

15. MODULE- 2 CTD Summaries
Module 2 should contain 7 sections in the following order :
• CTD Table of Contents
• CTD Introduction
• Quality Overall Summary
• Nonclinical Overview
• Clinical Overview
• Nonclinical Summary
• Clinical Summary
The organisation of these summaries is described in guidelines for M4Q, M4S, and M4E.

16. MODULE-3 QUALITY
Consists of detail information on Drug Substance [API] & Drug Product [FP]
Consists of detail information on Drug Substance [API] & Drug Product [FP]
Drug Substance part broadly covers:
1. General Information
2. Manufacture
3. Characterisation
4. Control of drug substance
5. Reference standard
6. Container closure system
7. Stability
Drug Product part broadly covers:
1. Description and Composition
2. Pharmaceutical Development
3. Manufacture
4. Control of excipients
5. Control of drug product
6. Reference standard
7. Container closure system
8. Stability

17. MODULE- 4 NON CLINICAL STUDY REPORTS
• Contains non clinical data
• Study Reports on
1. Pharmacology
2. Pharmacokinetics
3. Pharmacokinetic drug interactions (nonclinical)
4. Other pharmacokinetic studies
5. Toxicology (Genotoxicity, Carcinogenicity, Teratogenecity, Genotoxicity/Mutagenicity etc.)
6. Other studies

18. MODULE-5 CLINICAL STUDY REPORTS
• Contains clinical data
• Study reports on:
1. Reports of studies pertinent to pharmacokinetics using human
2. Biomaterials
3. Reports of human pharmacokinetic (PK) studies
4. Reports of human pharmacodynamic (PD) studies
5. Reports of efficacy and safety studies
6. Reports of postmarketing experience
7. Case report forms and individual patient listings

19. REGULATED COUNTRIES
Regulated market comprises of the following:
1. U.S.A.
2. Europe (28 EU nations)
3. Canada
4. Australia
5. New Zealand
6. Singapore
7. Japan
8. South Africa

20. SEMI REGULATED COUNTRIES
The semi regulated markets comprises of the Rest of the World namely:
1. Asia (Srilanka, Myanmar, Bangladesh, Thailand, Malaysia, Philippines,Vietnam)
2. Africa (Kenya, Uganda, Nigeria, Algeria, Zambia)
3. Middle East (Gulf Co-operation Council countries i.e. Bahrain, Kuwait, Oman,
Qatar, Saudi Arabia, UAE)
4. Latin America (Mexico, Brazil, Panama, Peru, Guatemala, Argentina, Chile,
Dominican Republic)
5. Russia CIS (common wealth of independent states)

21. REGULATORY BODIES (REGULATED MARKETS)
1) U.S.A. – United States Food Department & Administration (FDA)
Europe:
2) U.K.– MHRA (Medicines & Healthcare Products Regulatory Agencies)
3) Germany – Bfarm
4) Sweden – Medical Product Agency
5) Ireland – HSE (Health Safety Executive)
6) Netherlands – MEB (Medicines evaluation Board)
7) France – HAS (Haute Authorite de Sante)

22. COUNTRY
FOOD / DRUG REGULATORY AUTHORITIES /
AGENCIES
WEBPAGE/LINK
EUROPE European Medicine Agency http://www.emea.eu.int
CANADA Health Canada http://www.hc-sc.gc.ca
AUSTRALIA Therapeutic Goods Administration http://www.tga.gov.au
NEW ZEALAND
Australia New Zealand Joint Therapeutic Products
Agency Health and Ageing
http://www.tgamedsafe.org
Medsafe http://www.medsafe.govt.nz
SINGAPORE (ASEAN MEMBER) Ministry of Health http://www.hsa.gov.sg
JAPAN National Institute of Health Sciences (NIHS) http://www.nihs.go.jp
SOUTH AFRICA Medicines Control Council http://www.mccza.com/
INDIA Central Drugs Standard Control Organization http://www.cdsco.nic.in
CHINA State Food and Drug Administration http://www.sfda.gov.cn
HONG KONG Department of Health: Pharmaceutical Services http://www.psdh.gov.hk
ISRAEL Ministry of Health http://www.health.gov.il

23. COUNTRY
FOOD / DRUG REGULATORY AUTHORITIES /
AGENCIES
WEBPAGE/LINK
PHILIPPINES (ASEAN MEMBER) Bureau of Food and Drugs http://www.bfad.gov.ph
MALAYSIA (ASEAN MEMBER) Ministry of Health http://dph.gov.my
MYANMAR (ASEAN MEMBER) Ministry of Health http://www.dph.gov.my
POLAND Narodowy Instytut Zdrowia Publiccznego http://www.il.waw.pl
SINGAPORE (ASEAN MEMBER) Ministry of Health http://www.hsa.gov.sg
TAIWAN Bureau of Food and Drug Analysis http://www.nlfd.gov.tw
THAILAND (ASEAN MEMBER) Food and Drug Administration http://www.fda.moph.go.th/
UNITED ARAB EMIRATES Ministry of Health http://www.moh.gov.ae
VIETNAM (ASEAN MEMBER) Boy te Ministry of Health http://www.moh.gov.vn

24. USFDA

25. TYPES OF APPLICATIONS
 DRUG MASTER FILE (DMF)
 INVESTIGATIONAL NEW DRUG APPLICATION (IND)
 NEW DRUG APPLICATION (NDA)
 ABBREVIATED NEW DRUG APPLICATION (ANDA)

26. DRUG MASTER FILE (DMF)
• DMF is a submission to the FDA
• Usually concerning the CMC of a component of a drug product
• There is no legal or regulatory requirement to file a DMF
• Normally the CMC for a compendial excipient is not reviewed
• The DMF will be reviewed ONLY when it is referenced in an Application or another
DMF
• The holder MUST submit an LOA (2 copies) to the DMF
• THEN send a copy to the APPLICANT
• The applicant submits copy of LOA in their Application. This is the ONLY mechanism
to trigger review of the DMF

27. Types of DMFs
Originally Five Types
I - Manufacturing plant information (No longer acceptable by FDA)
II - Drug substance, drug substance intermediates and material used in their manufacture
III - Packaging material
IV - Excipients, colorant, flavor
V - FDA accepted reference information (FDA discourages its use)

28. Who is Who?
• The person or company who submits a DMF is the HOLDER
• The person or company who represents a DMF HOLDER is the AGENT
• The person or company who references the DMF is the APPLICANT or the
CUSTOMER or the AUTHORIZED PARTY (AP)
Reason for DMF
• To Maintain confidentiality of proprietary information (e.g., Manufacturing
procedure) for the holder
• Permit review of information by reviewers in the CDER to support applications
submitted by one or more applicants

31. INVESTIGATIONAL NEW DRUG APPLICATION (IND)
 Means through which the sponsor technically obtains exemption from the FDA
to distribute or transport the new drug under evaluation
 Application must contain the following information:
 Manufacturing information
 Animal Pharmacology & Toxicology Studies
 Clinical protocols and Investigator information
 Once the IND is submitted, the sponsor must wait 30 calendar days before
initiating any clinical trials

32. NEW DRUG APPLICATION (NDA)
 Means through which the drug sponsor seek approval from the FDA to sale & market a
new pharmaceutical in US
 Factors considered by 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.
 Human Clinical Trials data becomes part of NDA

33. ABBREVIATED NEW DRUG APPLICATION (ANDA)
 Means through which the applicant seek approval from the FDA to manufacture
and market a safe, effective, low cost alternative (the generic drug ) in US
 Termed as abbreviated because the preclinical (animal) and clinical (human)
data to establish safety and effectiveness is not needed

34. WHAT IS A GENERIC DRUG?
 Generic products rely on the findings of safety and efficacy of the innovator
drug after expiration of certain patents and exclusivities
 Generic drugs are copy versions of brand drugs.
 Generic drugs are safe and effective alternatives to branded drugs.
 “Equal quality” at “Low cost”
 Therapeutically equivalent = Phamraceutical equivalent + Bio equivalent

35. GENERIC DRUG REVIEW
1. Pharmaceutical Equivalence: The generic drug must have
• same active ingredient(s)
• same labeled strength
• same dosage form
• same administration
2. The drug company must show the generic drug is “Bioequivalent” to the brand-name drug
• active ingredient works in the same way
• active ingredient works in the same amount of time

36. GENERIC DRUG REVIEW
3. The generic drug’s labeling must be basically the same as that of the approved brand-
name drug (RLD)
4. The drug company must:
• fully document the generic drug’s chemistry, manufacturing steps, and quality control
measures
• detail each step of the process
5. The raw materials and the finished product must meet USP specifications, if applicable

37. GENERIC DRUG REVIEW
6. The drug company must:
• show that its generic drug maintains stability as labeled before it can be sold
• continue to monitor drug’s stability
7. The drug company must:
• comply with federal regulations for cGMPs
• give a full description of the facilities it uses to manufacture, process, test, package,
label, and control the drug
8. Inspection at the proposed manufacturing site ensures that the firm:
• is capable of meeting commitments of the application
• can manufacture the product consistently
• USFDA visits every two years

38. FDA REQUIREMENTS
Brand Name Drug
NDA Requirements
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Animal Studies
7. Clinical Studies
Generic Drug
ANDA Requirements
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Bioequivalence

39. ANDA
Y
N
N
Y Y YY
Generic
Drug Review
Process
Bioequivalence
Review
Labeling ReviewChemistry & Micro
Review
Request for Plant
Inspection
APPLICANT
Acceptable &
Complete
Application Review
N Chem/Micro
OK?
Labeling
OK?
Bioequivalence
OK?
PreApproval
Inspection Results
OK?
Not Approvable
Letter
Approval
Withheld until
Results
Satisfactory
Bio Deficiency
Letter
APPROVED
ANDA
NN
Refuse to Receive
Letter

40. ORANGE BOOK
• All FDA approved drug products listed (NDA’s,
OTC’s & ANDA’s)
– Therapeutic equivalence codes
“A” = Substitutable
“B” = Inequivalent, NOT Substitutable
– Expiration dates: patent and exclusivity
– Reference Listed Drugs/brand drugs identified by
FDA for generic companies to compare with their
proposed products

41. PATENT CERTIFICATION
A certification on patent situation referred in Orange book
This certification must state one of the following:
PARA I : No patent information on the drug product
PARA II : The listed patents have expired
PARA III : The patent will expire on a stated date and generics will be launched
upon expiration
PARA IV : The listed patents are invalid, not infringed or not enforceable by the
manufacture, use or sale of the generic drug.

42. PATENT CERTIFICATION

43. REWARD TO 1ST ANDA FILER
• First ANDA filer with Paragraph IV - 180 day exclusivity period
• No other ANDA approval for subsequent generics for 180 days
• Measured from the earlier date of marketing or court decision

44. POST-APPROVAL CHANGES
• Level I (Minor) change
• Level II (Moderate) change
• Level III (Major) change
• Chemistry (A/C test, Stability)
• In Vitro dissolution/release
• In Vivo bioequivalence test / IVIVC
• Annual report
• Change being effected supplement
• Prior approval supplement
Level of
Change
Tests
Filing

45. EUROPE

46. European union member states
Belgium (BE) Greece (EL) Lithuania (LT) Portugal (PT)
Bulgaria (BG) Spain (ES) Luxembourg (LU) Romania (RO)
Czech Republic (CZ) France (FR) Hungary (HU) Slovenia (SI)
Denmark (DK) Croatia (HR) Malta (MT) Slovakia (SK)
Germany (DE) Italy (IT) Netherlands (NL) Finland (FI)
Estonia (EE) Cyprus (CY) Austria (AT) Sweden (SE)
Ireland (IE) Latvia (LV) Poland (PL) United Kingdom (UK)
European free trade association
Iceland (IS) Norway (NO)
Liechtenstein (LI) Switzerland (CH)

47. REGULATORY BODY - EMA
 European medical Agency (EMA):
 Decentralized body of EU with headquarters in London (going to move
Amsterdam)
 Protection and promotion of public and animal health, through the
evaluation and supervision of medicines for human and veterinary use
 There are six scientific committees works under EMA in EU and EEA-
EFTA

48. Committees of EMEA
Committee for Medicinal Products for Human Use (CHMP)
 Committee for Medicinal Products for Veterinary Use (CVMP)
 Committee for Orphan Medicinal Products (COMP)
 Committee on Herbal Medicinal Products (HMPC)
 Pediatric Committee (PDCO)
 Committee for Advanced Therapies (CAT)

49. MARKETING AUTHORIZATION PROCEDURES
 CENTRALIZED PROCEDURE (CP)
 NATIONAL PROCEDURE (NP)
 MUTUAL RECOGNITION PROCEDURE (MRP)
 DECENTRALIZED PROCEDURE (DCP)

50. CENTRALIZED PROCEDURE
 Applications made directly to the European Agency for the Evaluation of
Medicinal Products leading to the grant of a European marketing authorization
by the Commission
 Mandatory for:
 Products of recombinant DNA
 Hybridoma technology and controlled gene expression
 Orphan medicinal products
 All ‘Advanced Therapy Medicinal Products’–gene therapy, cell therapy and
tissue-engineered products
 For medicinal products containing a new active substance or innovative
medicinal product

51. NATIONAL PROCEDURE
 Marketing authorization in one particular EU country
 Approval time for drug product varies within member states of EU
 Applicable to abridged drug products
 Not applicable to biotechnology products
 Can also serve as the first phase of a Mutual Recognition procedure
 National abridged standard and complex applications takes approximately 210
days to be approved in UK

52. MUTUAL RECOGNITION PROCEDURE (MRP)
 Only applicable if the applicant already has a national marketing authorization
 Not applicable to (biotech) products
 Procedure:
 Application to Reference Member State (RMS)
 First authorization granted by RMS
 Applicant requests mutual recognition
 Dossier consolidated for submission to other “concerned Member States
(CMS)
 Approval from CMS within 90 days

53. DECENTRALIZED PROCEDURE (DCP)
 Available pathway if the product has no existing MA in any Member State
 Timeline for the DCP approval is 150 to 300 days
 Not applicable to (biotech) products
 Procedure:
 Identical dossiers sent to RMS and CMS
 RMS prepares preliminary assessment report and sends to CMS – Day 70
 CMS sends any comments to RMS –Day 100
 Clock-off period
 RMS prepares draft assessment report and sends to CMS – Day 120
 CMS sends any comments to RMS –Day 145
 RMS may close procedure if consensus reached –Day 150
 If RMS and CMS cannot reach agreement by Day 150 it referred to the
Coordination group for MRP and DCP for human medicinal products CMD (h)

54. VARIATIONS
TYPE 1 VARIATION
(NOTIFICATION)
TYPE II VARIATION
• Change in composition of the
finished product
• Change in immediate packaging of
the finished product
TYPE 1A VARIATION
• Change in the name of
the active substance
• Change in ATC code
• Change in name of
address of the marketing
authorisation holder
TYPE 1B VARIATION
• Change in the name of
medicinal product
• Change in retest period of
active substance
• Change in storage
conditions for active
substance

55. Differences between US & EU filing
Requirements US EU
Agency One Agency USFDA
Multiple Agencies
· EMA
· CHMP
· National Health Agencies
Registration Process One Registration Process
Multiple Registration Process
· Centralized (European Community)
· Decentralized (At least 2 member states)
· Mutual Recognition (At least 2 member states)
· National (1 member state)
TSE/BSE Study data TSE/BSE Study data not required TSE/BSE Study data required
Braille code Braille code is not required on labelling Braille code is required on labelling
Post-approval changes
Post-approval changes in the approved
drug:
· Minor changes
· Moderate changes
· Major changes
Post-variation in the approved drug:
· Type IA Variation
· Type IB Variation
· Type II Variation

56. Administrative Requirements
Requirements US EU
Application ANDA / NDA MAA
Debarment classification Required Not Required
Number of copies 3 1
Approval Timeline ~18 Months ~12 Months
Fees
$2 million-NDAApplication
$51,520 – ANDAApplication
National fee (including hybrid applications):
£103,059
Decentralised procedure where UK is CMS:
£99,507
Presentation eCTD & Paper eCTD

57. Finished Product Control Requirements
Requirements US EU
Justification ICH Q6A ICH Q6A
Assay 90 - 100 % 95 - 105 %
Disintegration Not Required Required
Colour Identification Not Required Required
Water Content Required Not Required

58. Manufacturing & Control Requirements
Requirements US EU
Number of batches 1 3
Packaging A minimum of 1,00,000 Units Not Required
Process Validation Not required at the time of submission Required
Batch Size 1 pilot scale or minimum of 1 lakh units
whichever is higher.
2 pilot scale plus 1 lab batch or
minimum of 1 lakh units whichever is
higher.

59. Stability Requirements
Requirements US EU
Number of
batches
3 Pilot Batches or
2 Pilot Batches & 1 Small scale
2 Pilot Scale (If API Stable),
3 Primary Batches
(If API unstable)
Condition:
Long term: 25°C/60%RH
Accelerated: 40°C/75%RH
Intermediate: 30°C/65%RH
Long term: 25°C/60%RH
Accelerated: 40°C/75%RH
Intermediate: 30°C/65%RH
Minimum time period at
Submission
6 Months Accelerate & 6 Months long term 6 Months Accelerate & 6 Months long term
Container orientation Inverted & Upright Do not address
Clause 21 CFR part 210 & 211
Volume 4 EU Guidelines for medicinal
products
QP Certification Not Required Required

60. Bioequivalence Requirements
Requirements US EU
CRO (Audits) Audited by FDA Audited by MHRA
Reserve Sample 5 times the sample required for analysis No such requirement
Fasted / Fed Must be as per OGD recommendation No such requirement
Retention of samples 5 years from date of filing the application No such requirement
BE study for generic drugs
Against US RLD in any country. To refer ‘BE
recommendations’ in FDA site for guidance.
Against EU reference product (ERP) in
any country