Explanatory presentation on drug regulatory affairs of various countries.

1. International
Drug Regulatory Affairs
Presented by:- Shipra Omar
M.Pharm 1st Semester
SGRRITS, D.Dun
1

2. Regulatory structure
• The pharmaceutical industry is one of the highly
regulated industries with various structures of
drug regulation
▫ Drug laws
▫ Drug regulatory agencies
▫ Drug evaluation boards
▫ Quality control laboratories
▫ Drug information centers
2

3. What is the need?
• Drug laws provide the basis for drug regulation
• Regulatory tools such as standards and
guidelines equip authorities with the practical
means of implementing those laws
• Regulatory Agencies monitor the
implementation of these laws
3

4. Regulatory Scenario
Regulated Markets Emerging Markets
• US
• Canada
• EU-27 states
• Japan
• Australia
• New Zealand
• Latin America
• Eastern Europe
• CIS
• Africa
• Asia Pacific
• Gulf countries
4

5. Regulatory Agencies
USA Food & Drug Administration (FDA)
Europe
The European Agency for the Evaluation of Medicinal Products
(EMEA)
Japan Ministry of Health, Labour & Welfare(MHLW)
Australia Therapeutic Goods Administration (TGA)
Brazil National Health Surveillance Agency (ANVISA)
Nigeria
National Agency for Food and Drug Administration and Control
(NAFDAC)
China State Food and Drug Administration (SFDA)
India Central Drugs Standard Control Organization (CDSCO)
Uganda Uganda National Council for Science and Technology (UNCST)
International
International Conference on Harmonization (ICH)
World Health Organization (WHO)
5

6. Obstacles
• Pharmaceutical, Non-clinical and Clinical issues
emerge in all stages of development
• Regulatory guidelines don’t always address
problems encountered
• Language barrier
• Bureaucracy
• Political environment
9

7. Registration Procedure of Drugs
for International Marketing
10

8. Drug Approval Process
• A regulatory process by which a
person/organization/sponsor/innovator gets
authorization to launch a drug in the market
11

9. Various Stages
• Application to conduct clinical trials
• Conducting clinical trials
• Application to marketing authorization of drug
• Post-marketing studies
12

10. 13

11. 14
Vendor Selection
Approved API Excipients Packing Material
Plant inspection
API Plant
Inspection
BE studies approved
CRO
Test, Import &
Manufacturing License
Patent/ development
Strategy
BE Strategy
Finished Product
Development
Dossier Writing
Regulatory Filing to Authorities
Dossier Evaluation
Product Approval

12. Common Technical Document (CTD)
16
Required for generics and New Drug
• Required for generics and New Drug.
• For generics summary on Quality part only
required
• Summarizes Module 3, 4 and 5
• Provides abstract of documents
provided in the whole application
• Required for generics
and New Drug
• Documents related to
Chemistry,
manufacturing and
Control of both Drug
Substance and Drug
Product
• Data on pharmacologic, pharmacokinetic,
and toxicological evaluation of the
pharmaceutical product
• Not required for generics
• Critical assessment of
the clinical data and
related reports
• Generics require only
BE study
• Consists of documents like
Application form, legal
documents (GMP, Licences etc.),
labelling etc.

13. 17
Zone Type of Climate
Zone I Temperate zone
Zone II Mediterranean/subtropical zone
Zone III Hot dry zone
Zone IV Hot humid/tropical zone
Zone IVb ASEAN testing conditions hot/higher humidity
Climatic Zone Temperature Humidity Minimum Duration
Zone I 21ºC ± 2ºC 45% rH ± 5% rH 12 Months
Zone II 25ºC ± 2ºC 60% rH ± 5% rH 12 Months
Zone III 30ºC ± 2ºC 35% rH ± 5% rH 12 Months
Zone IV 30ºC ± 2ºC 65% rH ± 5% rH 12 Months
Zone IVb 30ºC ± 2ºC 75% rH ± 5% rH 12 Months
Refrigerated 5ºC ± 3ºC No Humidity 12 Months
Frozen -15ºC ± 5ºC No Humidity 12 Months
Climatic Zone Temperature Humidity Minimum Duration
Accelerated Ambient 40ºC ± 2ºC 75% rH ± 5% rH 6 Months
Accelerated Refrigerated 25ºC ± 2ºC 60% rH ± 5% rH 6 Months
Accelerated Frozen 5ºC ± 3ºC No Humidity 6 Months
Intermediate 30ºC ± 2ºC 65% rH ± 5% rH 6 Months
Accelerated and Intermediate Testing Conditions
ICH Stability Zones
Long Term Testing Conditions

14. COUNTRY SPECIFIC GUIDELINES
18

15. Regulatory Agency
• Food & Drug Administration
• Main consumer watchdog in this system is FDA's
Center for Drug Evaluation and Research
(CDER)
19

16. Laws, Regulations, Policies &
Procedures
• The Federal Food, Drug, and Cosmetic Act (1938)
▫ With numerous amendments it is the most extensive
law of its kind in the world
• Code Of Federal Regulations (CFR)
▫ Section 21 of the CFR contains most regulations
pertaining to food and drugs
• Manual of Policies and Procedures (MaPPs)
▫ Approved instructions for internal practices and
procedures followed by CDER staff to help standardize
the new drug review process and other activities
20

17. Types of Applications under Sec 505
• New Drug Application (NDA)
• Abbreviated New Drug Application (ANDA)
21

18. New Drug Application (NDA)
22
505 (b) (1)
MA for New
Chemical
Entities (NCE)
505 (b) (2)
MA for changes
to an approved
drug (Change in
dosage form,
strength,
indication etc.)

19. NDA
• Since 1938, every new drug has been the subject of an
approved NDA before 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 U.S.
• The data gathered during the animal studies and human
clinical trials of an Investigational New Drug (IND)
become part of the NDA.
• Generally approval of an NDA is granted within two
years (on an average), however, this process can be
completed from two months to several years.
23

20. Applicable Regulations, Policies &
Procedures (NDA)
• 21CFR Part 314 - Applications for FDA Approval to Market
a New Drug or an Antibiotic Drug.
• MaPPs
▫ 5015-6:Review of the Same Supplemental Change to More than
One NDA or ANDA in More Than One Review Division
▫ 6010.5:NDAs: Filing Review Issues
▫ 6020.8: Action Packages for NDAs and Efficacy Supplements
▫ 6050.1: Refusal to Accept Application for Filing From Applicants
in Arrears
▫ 7211.1: Drug Application Approval 501(b) Policy
▫ 7600.6: Requesting and Accepting Non-Archivable Electronic
Records for New Drug Applications.
24

21. Abbreviated New Drug Application
(ANDA)
25
Paragraph I
For the products for which no
patent information is available in
the orange book
Paragraph II
Used for the products for which all
the applicable patents are expired
Paragraph III
Used for the patent products
where the applicant confirms that
the product will not be placed in
the market till such patents are
expired
Paragraph IV
Used for patented products where
applicant files the product which
does not infringe the patent.
Successful applicant enjoys
6month exclusivity
505 (j)
MA of generics

22. ANDA
• Applications are termed "abbreviated" as preclinical and
clinical data is not required
• Reviewers focus on bioequivalence data, chemistry and
microbiology data, requests for plant inspection, and
drug labelling information.
• A generic drug must be comparable to an innovator drug
in dosage form, strength, route of administration,
quality, performance characteristics and intended use
• Once approved, an applicant may manufacture and
market the generic drug product to provide a safe,
effective, low cost alternative to the American public
26

23. Applicable Regulations, Policies &
Procedures (ANDA)
• 21CFR
▫ Part 314 : Applications for FDA Approval to
Market a New Drug or an Antibiotic Drug
▫ Part 320 : Bioavailability and Bioequivalence
Requirements
▫ Part 310 : New Drugs
• MaPPs:
▫ Chapter 5200 - Generic Drugs
27

24. Data requirements
28
Site Registration Yes
Plant GMP approval US FDA Audit of both API and FP manufacture
Stability Zone Zone I & II
Stability Requirements 25 ± 2 C; 60% ± 5% RH
No. of submission batches
One pilot scale or minimum 100,000 units whichever is
higher
Stability guidelines reference ICH
Stability data 3 months
BE study for generics
Against US reference listed drug (RLD) in any country
by USFDA app CRO
Major Holdup Patent non-infringement, FDA audit, competition
Dossier format CTD
Registration time 12-24 months

25. 29
Drug Registration Process in US
Pre NDA Meeting
9-12 months prior to NDA submission
Filing of NDA to FDA
Application sent to CDER
Checking Application
Sent to Reviewer
Submit review report to CDER
Issue Marketing Authorization
Notify the applicant
about deficiency
Submission of
amended application
Review of amended
application
Rejection of
Application
Inform Applicant
Within 180 days
+ve
Not OK
OK
-ve
-ve
+ve

26. COUNTRY SPECIFIC GUIDELINES
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27. Regulatory Agencies
• EMEA
• Committee for Human Medicinal Products (CHMP)
31

28. Types of Procedures
• Centralized Procedure
• Decentralised Procedure
• Mutual Recognition Procedure
• National Procedure
32

29. Centralized Procedure
• When used
▫ Used for biologic products or other products using high-
technology procedures
▫ Products for HIV/AIDS, cancer, diabetes,
neurodegenerative disease, auto-immune or other
dysfunctions, and viral diseases
▫ Products for orphan conditions
▫ Other new active substances at the request of the applicant
• Pros
▫ One application applies to all countries in the EU.
▫ Relatively quick procedure.
▫ A positive outcome is very beneficial to the sponsor.
• Cons
▫ A negative outcome will affect access to the entire EU
33

30. 34
Pre-Application
Validation
CHMP scientific
assessment and
opinion
Possible appeal
Decision-making
process
EMA notified
Rapporteur/ Co-rapporteur appointed
Application - validation
CHMP scientific assessment
CHMP opinion
Applicant Appeal European Commission
Draft Commission
Decision
Standing Committee
-120
Days
14
Days
210
Days
120
Days
+90-
110
Days
Unfavourable Favourable
Decision approving
Community
authorization
Centralized Procedure Guidelines

31. Decentralised Procedure
• When used
▫ Used for products that fall outside the scope of the
EMA centralized procedure.
• Pros
▫ Simultaneous authorization in numerous countries in
the EU.
▫ May be more efficient than national authorization
since a positive outcome results in numerous country
approvals.
▫ Sponsor can select which countries to apply to; does
not have to be all EU countries.
• Cons
▫ A negative decision on an application may affect
numerous countries.
35

32. 36
Application filed
to CMS & RMS
chosen
Validation of
Application by
CMS (14 days)
RMS assesses
the application
(120 Days)
Report sent to
CMS & applicant
CMS assess
application
(90 Days)
Report to co-
ordination
working group
(60 days)
EMEA/CHMP
assess
application
(60 days)
Member state
having objection
refuse to grant
MA
National MA
Granted
Objection
No Objection
Objection
No
Objection
Objection
not
solved
Objection solved
Objection
not
solved
Communicate to
RMS, CMS &
Applicant
Objection solved
Report sent
to Applicant
Decentralized Procedure Guidelines

33. Mutual Recognition Procedure
• When used
▫ Individual application to one country within the EU
for products that fall outside the scope of the EMA
centralized procedure.
• Pros
▫ Review by one country and other countries accept the
decision.
▫ Only one application needs to be submitted.
• Cons
▫ Individual national approvals can add significant time
to the process.
▫ A negative outcome can affect numerous countries
37

34. Procedure Guidelines
• Similar to the de-centralized procedure with some differences.
• MRP is applicable to medicinal products which have received a
marketing authorization in any member state whereas the
decentralized procedure is applicable to those products which
were never approved in any member states of the European
Union.
• The evaluation of application by RMS can be taken within 90
days instead of 120 days (in decentralized procedure).
• After the grant of marketing authorization, the product can be
marketed, which may be called as Phase IV trials, wherein new
uses or new populations, long-term effects etc. can be explored.
38

35. National Procedure
• When used
▫ Individual applications to each country within the
EU.
▫ Used for products that fall outside the scope of the
EMA centralized procedure.
• Pros
▫ If application rejected in one country, can still
access other EU countries.
• Cons
▫ Separate applications required for each country.
▫ Unique requirements and formats may be
required.
39

36. Procedure Guidelines
• This type of authorization is granted on country-
by-country basis by the competent authorities,
in each member state.
• Each country within the EU has its own
procedures for authorizing a marketing
application for a new drug.
• A sponsor can consult the website of the
regulatory agency in each country in which it is
interested in obtaining marketing approval to
obtain details of the approval process.
40

37. Data requirements
41
Plant GMP approval Audit by any member states of EU
Stability Zone Zone I & II
Stability Requirements 25 ± 2 C; 60% ± 5% RH
No. of submission batches 2 pilot scale + 1 lab batch
Stability guidelines reference ICH
Stability data 6 months
BE study for generics
Against European Reference Product (ERP) in any
country. Fed, Fast and Steady state required.
Major Holdup
Patent non-infringement, GMP audit, high cost
of registration, maintenance of registration,
Administrative procedures for each member states.
Dossier format CTD
Registration time
As per the procedure (DCP, MRP) schedule,
Usually 12-18 months

38. COUNTRY SPECIFIC GUIDELINES
42

39. Regulatory Agency
• MHLW
• Pharmaceutical and Medical Devices Agency
(PMDA)
▫ NDA/ANDA Application
▫ Review of GCP/GMP on-site inspection
• P’ceutical affairs & food sanitization council
(PAFSC)
▫ Consultation on Review Data
43

40. Data requirements
44
Site Registration Yes
Plant GMP approval Audit by PMDA of both FP and API sites
Stability Zone Zone II
Stability Requirements 25 ± 2 C; 60% ± 5% RH
No. of submission batches 3 pilot scale
Stability guidelines reference ICH
Stability data 12 months
BE study for generics Against Japan reference drug in any country
Major Holdup
Stand alone development, Quality by Design in
practice, translations, generic acceptance
Dossier format CTD
Registration time 18-24 months

41. 45
Drug Registration Process in Japan
New Drug Approval
Application
PMDA
Approval Review
Compliance Review
GMP review
PAFSC
Evaluation Committees
P’ceutical Affairs
Section
ExpertsNomination
Consultation
Advice
Inquiry
Response
Notice of Review Results
MHLW
(Evaluation & Licensing Div, PFSB)
Minister of MHLW (Final Evaluation)
PFSB: P’ceutical and Food Safety Bureau
Approval & entry in NHI Price List

42. COUNTRY SPECIFIC GUIDELINES
46

43. Regulatory Agency
• The TGA regulates therapeutic goods through:
▫ Pre-market assessment
▫ Post-market monitoring and enforcement of standards
▫ Licensing of Australian manufacturers and verifying
overseas manufacturers' compliance with the same
standards as their Australian counterparts
• Australian Drug Evaluation Committee (ADEC)
▫ Gives advice for new medicines
• Drug Safety and Evaluation Branch (DSEB)
▫ NDA/ANDA Application
47

44. Guidelines
• An application is submitted to TGA to register the drug
in Australian Register of Therapeutic Goods (ARTG)
after the completion of clinical trials.
• The application consists of data to support the quality,
safety and efficacy of the product for its intended use.
• The application is assessed (on an administrative level)
to make sure for compliance with basic guidelines and
further evaluated by different sections and advice can
also be sought on key issues to take final decision.
• A company can make comments on the evaluation
report, if necessary.
48

45. 49
Preparation & submission of Application to
DSEB of TGA
Application reviewed by entry review team
Evaluation of Application
Accepted
-ve
Sent back to
Applicant
Within 225 days
Report sent to TGA delegates
Delegates seek advice of ADEC
Delegates make final decision noting any
recommendation from ADEC
Approval of Drug
Sent to
Applicant
Applicant comments on the
report and submits
supplementary data
Applicant has an opportunity to
comment on delegates report
Drug Registration Process in Australia

46. COUNTRY SPECIFIC GUIDELINES
50

47. Regulatory Agency
• State Food and Drug Administration (SFDA)
• Provincial Drug Administration Authorities (PDAAs)
▫ Organize the works of the formal review of submitted
materials
• Centre for Drug Evaluation (CDE)
▫ Evaluate the submitted information
51

48. Drug Approval Process
• After formal review, the PDAAs send the qualified applications to
the SFDA for further review.
• The import drug registration application should be directly
submitted to SFDA by the applicant.
• SFDA’s Department of Drug Registration carefully reviews the
completeness of the submitted materials, files the qualified
applications and transmits all the materials of qualified applications
to the directly attached to SFDA.
• CDE determine whether the safety and effectiveness information
submitted for a new drug are adequate for manufacturing and
marketing approval and send the report of review to SFDA.
• SFDA carefully considers the recommendations of CDE and makes
a decision whether or not the drug registration application can be
approved and issues the certificate of drug approval and drug
approval number to the qualified applicant.
52

49. 53
Dossier transferred from CDE to
SFDA for administrative approval
Regulatory approval granted
Filing drug registration application to PDAA
Application sent to SFDA for reviewing the completeness
Dossier transferred from SFDA to CDE for technical review
After formal review
Within 30 working days
If complete within 120 days
Within 30 days
Notify applicant for deficiency
Resubmission of amended application by
applicant
Technical review report of amended
application by CDE
Opinion of CDE on technical review
Refusal to Proceed
If not complete
Within 4 months
Within 40 days
+ve
-ve
New Drug Registration Process of China

50. COUNTRY SPECIFIC GUIDELINES
54

51. Markets
• Brazil, Mexico, Venezuela , Ecuador and Colombia are some of
the major pharmaceutical markets
• Brazil and Mexico considered Regulated Markets
• ANVISA : Stringent norms comparable to USFDA
• Brazil : As per ANVISAs norms, CROs used for BE studies
have to be approved and certified by the Brazilian authority.
• For BE studies, innovator product manufactured in Brazil has
to be used for comparison
• ANVISA has implemented generic law to facilitate generic
market entry into the country
• Mexico: Extensive analytical raw data of 3 stability batches.
• Venezuela : Copies of source data
55

52. Drug Regulatory Requirements -
Technical
• Manufacturing Formula and Justification
• Manufacturing Process
• Process Validation
• Batch Numbering
• Batch Records
• Stability Studies (Source Data)
▫ Accelerated
▫ Long Term
56

53. Drug Regulatory Requirements - Legal
• Free Sale Certificate / Product Permission
• GMP Certificate
• Manufacturing License
• Power of Attorney / Contract
• Trademark Registration
• Contract with local quality control facility
57

54. Critical Success Factors
• US FDA / UK MCA / TGA approved facilities
• Strong Regulatory Support
• Good Distribution Set up
• Price Competitiveness
• Good Marketing Support
• Strong group for registering products in place
• Expansion in new markets and new products under
feasibility studies
58

55. Stability Issues
• Common Technical Document (CTD) norms are taken as
guidance for regulatory aspects during drug development
• Major discrepancies in requirements of storage conditions for
various countries
• Stability studies on three batches - as per ICH guidelines /
individual country norms
▫ Brazil: 30 ± 2 C; 75% ± 5% RH
▫ Colombia, Peru, Ecuador:30 ± 2C / 65% ± 5% RH
▫ Others: 25 ± 2 C; 60% ± 5% RH
59

56. Data requirements
60
Site Registration Yes
Plant GMP approval Major countries do audit. (Brazil, Mexico, Colombia)
Stability Zone Zone II & Zone IVb
Stability guidelines reference ANVISA and ICH
Stability data 6– 12 months
BE study for generics
Brazil: Against Brazil reference drug in any CRO
approved by ANVISA. PE to be done in Brazil
Mexico: Against Mexican reference, in Mexico Only.
Others: The BE for Brazil /Mexico is normally
accepted.
Major Holdup
Certificate of P’ceutical Pdt., Legalizations,
Translations, GMP audits, local requirements, time
delay
Dossier format Country specific

57. Time and cost for registering a drug
Country Number of
months
Cost in US dollars (2003)
Argentina 3-4 $1,000 for original; $333 for generic/similar
Bolivia 1 $50
Brazil Original = 12-14
similar = 8-12
generic = 6-8
$2,700-27,000 for original (the price depends on
the size of the manufacturer); $7,000 for a similar;
$2,000 for a generic
Colombia New = 6
Similar/generic = 3
$1,200 new; $1,000 re-validation
Chile 8-12 $1,300 for original ; $800 for generics/similars
Ecuador 1 $1,339 foreign; $535 national; $344 essential
Nicaragua 3 $485 foreign; $166 national
Peru 7 days $89
Uruguay 46 $500
61

58. COUNTRY SPECIFIC GUIDELINES
62

59. Guidelines
• Russia has its own, unique regulatory system which does not
correspond to U.S. or EU practices.
• Cultural and language barriers often become a challenge to
foreign companies attempting to register pharmaceuticals by
themselves
• Registration procedure is also quite complicated and the
documents tend to be modified due to constant changes in the
regulatory requirements.
• Before exporting a pharmaceutical product to Russia it has to
be registered at the Ministry of Health of the Russian
Federation; Department for registration of pharmaceuticals of
the Federal Service for Health Control
63

60. Registration Procedure
• The best way to accomplish registration of a
pharmaceutical product in Russia is trough one
of the following types of companies:
▫ Company incorporated in Russia and belonging to
the Indian parent company
▫ Russian distributor/authorized agent
▫ Consulting company
64

61. Documentation
• For the registration procedure a company has to
submit the following:
▫ General documents
▫ Certificates
▫ Information and test reports
▫ Samples and package
65

62. General documents
• Application for the State registration of a pharmaceutical
which includes the name of the pharmaceutical preparation,
the name and the contact information of the manufacturer
• Name of the pharmaceutical preparation, including
international non-proprietary name, scientific name in Latin,
trade name and main synonyms
• List of active ingredients and components
• Recommended dosage, instruction for use
• Description of the drug and its packaging, shelf life and
storage conditions
• Power of Attorney issued by the manufacturer to the
authorized company for carrying out registration procedure
(notarized original with apostil)
66

63. Certificates
• Copy of Free Sales Certificate (must be notarized and apostilled)
• Copy of the license of pharmaceutical manufacture (must be notarized and
apostilled)
• Copy of GMP certificate (must be notarized and apostilled)
• Copy of Certificate of manufacturer registration in their own country (must
be notarized and apostilled)
• Original of Certificate of analysis of the drug and its active substance (must
be signed and stamped by manufacturer)
• Copy of Certificate of trade mark (must be signed and stamped by the
manufacturer)
• Information of registration of the drug in the country of the manufacture
and in other countries
• A certificate of analysis of the drug in the country of origin of the
manufacturer, GMP certificate and information on registration of the drug
in the foreign country.
67

64. Information and test reports
• Summary of the method of the drug manufacturing (must be
signed and stamped by manufacturer)
• Complete description of the quantitative and qualitative
control methods with references to the pharmacopoeia and
specification (must be signed and stamped by manufacturer)
• Stability data of three drug series – by date
• Patterns of the spectrums and chromatograms of the drug
• Report of the pharmacological (specific) activity study
substantiated the indications for use which are formed and
described in the instruction
• Test report of the drug toxicity (acute, sub acute, sub chronic,
chronic toxicity)
68

65. Information and test reports
• Test report of the specific influences (cancerogenity, mutagenic and
teratogenic effects, embryotoxicity, allergic and local-irritative
effects)
• Clinical trial report of the medicine usage in clinic (the information
which concerns only the drug that is produced by this
manufacturer)
• Copies of publications of the medicine usage in clinics after its
registration in the country of origin (the information which
concerns only the drug that is produced by this manufacturer)
• Report of pharmacokinetics of the pharmaceutical study and its
bioequivalence to the original drug
• Summary information of the side effects, in comparison with other
analogous medicines, used at the same indications
• Instruction for use (must be signed and stamped by the
manufacturer)
69

66. Samples and package
• Information of the material used for package:
Certificates of the packaging materials (must be
signed and stamped by the manufacturer)
• Colour design of internal and external packages
(Original and Russian version)
• Standard samples of the active substance for
quality control
• Standard and referenced samples of the drug for
the binding examination of quality (should be in
the standard package)
70

67. Approval Procedure
• The Ministry of Health determines whether
these approvals are sufficient for an exemption
of the drug from clinical and other testing in
Russia before issuing a registration certificate.
• Officially Russia does not recognize FDA and EU
certificates.
• According to the Law on Medicines, a fee in form
of a state duty is to be paid for state registration
and the registration should take no longer than
six month.
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68. THANK YOU FOR LISTENING
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