ICH guidelines

about all ich guidelines by pavani

1. International Conference on International Conference on
Harmonization (ICH)Harmonization (ICH)

2. INTERNATIONAL CONFERENCE OF INTERNATIONAL CONFERENCE OF
HARMONIZATION (ICH)HARMONIZATION (ICH)
By
G.PAVANI,
Y17MPHPA426 ,
DEPT OF PHARMACEUTICAL
ANALYSIS
CLPT

3. ICH GuidelinesICH Guidelines
ICH is neither a forum of global
politics nor a trade negotiation,
but a scientific forum
ICH covers “new drugs”
ICH guidelines provide “how to
collect data scientifically for
marketing authorization”

4. Philosophy/PurposePhilosophy/Purpose of ICHof ICH
 Eliminate Duplication in Tests to
meet Different Regulatory
Requirements
 More Efficient Use of Resources
 Timely Access of Patients to
Safe and Effective “New Drugs”

5. What Does the Pharmaceutical What Does the Pharmaceutical
industry do?industry do?
chemists
biologists
molecular geneticists
drug metabolists
pharmacists
clinicians
statisticians
patents
marketing/sales
and many more!!

6. ICHICH

7. ICH Conferences ICH Conferences
ICH 1 - Nov1991 - Brussels
ICH 2 - Oct 1993 - Orlando ,Florida
ICH 3 - Nov 1995 - Yokohama, Japan
ICH 4 - July 1997 - Brussels
ICH 5 - Nov 2000 - San Diego - US
ICH 6 - Nov 2003 - Osaka, Japan
ICH 7 - 2007 - Europe ? Cancelled ?
ICH Public meetings ………..ICH Steering
Committees ----
Regional meet with non-profit organizations

8. Working Groups
SAFETY EFFICACY
QUALITY MULTIDISCIPLINARY
STEERING COMMITTEE
Endorses topics, guidelines and monitors
progress

9. Qs, Ss Es and Ms
Q1………………………… Q11
S1………………………….S8
E1………………………….E14.
M1…………………………M6

10. Quality :Q1 to Q11
Q1- Stability
Q2- Analytical validation
Q3- Impurities
Q4 – Pharmacopoeias
Q5- Quality of Biotechnological products
Q6 – Specifications
Q7 – GMP for APIs
Q8 – Pharmaceutical development
Q9- Quality Risk Management
Q10 – ‘Quality Management’ agreed ‘in principle’
Q 11-DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES (CHEMICAL ENTITIES AND
BIOTECHNOLOGICAL/BIOLOGICAL ENTITIES )

11. Q1
Stability
Q1A(R2)
Stability Testing of New Drug Substances and Products
Q1B
Stability Testing : Photostability Testing of New Drug Substances and Products
Q1C Stability Testing for New Dosage Forms
Q1D
Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products
Q1E Evaluation of Stability Data
Q1F
Stability Data Package for Registration Applications in Climatic Zones III and IV

12. Q2
Analytical Validation
Q2(R1) New title:

Validation of Analytical Procedures: Text and Methodology

13. Q3
Impurities
Q3A(R1) Impurities in New Drug Substances
Q3B(R2) Impurities in New Drug Products
Q3C(R3)
Impurities: Guideline for Residual
Solvents

14. Q4
Pharmacopoeias
Q4 Pharmacopoeias
Q4A Pharmacopoeial Harmonisation
Q4B Regulatory Acceptance of Analytical
Procedures and/or Acceptance Criteria
(RAAPAC)

15. Q5
Quality of Biotechnological Products
Q5A(R1)
Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin
Q5A Q5B
Quality of Biotechnological Products : Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products
Q5B Q5C
Quality of Biotechnological Products : Stability Testing of Biotechnological/Biological Products
Q5C Q5D
Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products
Q5D Q5E
Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process

16. Q6
Specifications
Q6A
Specifications : Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (including Decision Trees)
Q6B
Specifications : Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

17. Q7
Good Manufacturing
Practice
Q7 Good Manufacturing
Practice Guide for Active
Pharmaceutical
Ingredients

18. Q8
Pharmaceutical Development
Q8 Pharmaceutical Development

19. Q9
Quality Risk Management
Q9 Quality Risk Management

20. Risk Management across the
Product lifecycle for drug ( medicinal) products
Research
Preclinical
Phase
Clinical
Phases
Launch
Quality
ICH Q9
Safety
Efficacy
Manufacturing
& Distribution
GLP
GCP
GMP
GDP
End of
life cycle

21. Q10
‘Quality management’ agreed ‘in principle’
Waiting for Q9 to progress .

22. Q11
Q 11-Development and manufacture of drug
substances (chemical entities and
biotechnological/biological entities)

23. Regulatory or formal stability testing
•2006.01.09.•Dr. Pogány - Guilin
•23
/61
Storage temperature
(°C)
Relative
humidity
(%)
Minimum time
period covered by
data at submission
(months)
Accelerated: 40±2 75±5 6
Intermediate: 30±2 65±5 12
Long term: 25±2 60±5 12 (6)

24. Impurities
ICH Topic Q 3 B (R2)
Impurities in New Drug Products
Organic Impurities
Inorganic Impurities
Residual solvents
LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS
QUALIFICATION OF DEGRADATION PRODUCTS
Quantification of the degradants
Limits of impurities

25. Limits of impurities
Unspecified : NMT 0.1%
NMT 500 mcg /day intake

26. Efficacy : E1- E14
Clinical Safety
E1
The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions
E2A
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
E2B(R3)
Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports
E2C(R1)
Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs
E2D
Post-Approval Safety Data Management: Definitions and Standards for Expedite Reporting
E2E Pharmacovigilance Planning
Clinical Study Reports
E3 Structure and Content of Clinical Study Reports
Dose-Response Studies
E4 Dose-Response Information to Support Drug Registration

27. Efficacy
Ethnic Factors
E5 (R1) Ethnic Factors in the Acceptability of Foreign Clinical Data
Good Clinical Practice
E6(R1) Good Clinical Practice
Clinical Trials
E7 Studies in Support of Special Populations: Geriatrics
E8 General Consideration of Clinical Trials
E9 Statistical Principles for Clinical Trials
E10 Choice of Control Group and Related Issues in Clinical Trials
E11 Clinical Investigation of Medicinal Products in the Pediatric Population
Guidelines for Clinical Evaluation by Therapeutic Category
E12 Principles for Clinical Evaluation of New Antihypertensive Drugs
Clinical Evaluation
E14 The Clinical Evaluation of QT/ QTC Interval Prolongation and Pro arrhythmic
Potential for
Non- Anti arrhythmic Drugs

28. Safety:
Carcinogenicity studies
S1A : Need for Carcinogenicity studies for Pharmaceuticals
S1B : Testing for carcinogenicity for pharmaceuticals
SC1(R1) : Dose selection for carcinogenicity of Pharmaceuticals & Limit
dose
Genotoxicity studies
S2A Guidance on Specific Aspects ofRegulatory Genotoxicity Tests
for Pharmaceuticals
S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of
Pharmaceuticals
Toxicokinetics and Pharmacokinetics
S3A Note for Guidance on Toxicokinetics: The Assessment of
Systemic Exposure in Toxicity Studies
S3B Pharmacokinetics: Guidance for Repeated Dose Tissue
Distribution Studies

29. Safety
Toxicity Testing
Single Dose Toxicity Tests
S4 Duration of Chronic Toxicity Testing in Animals (Rodent
and Non Rodent Toxicity Testing)
Reproductive Toxicology
S5(R2) New title: Detection of Toxicity to Reproduction for
Medicinal Products & Toxicity to Male Fertility
Previously: Detection of Toxicity to Reproduction for
Medicinal Products
Biotechnological Products
S6 Preclinical Safety Evaluation of Biotechnology-Derived
Pharmaceuticals

30. Safety
Pharmacology Studies
S7A Safety Pharmacology Studies for Human Pharmaceuticals
S7BThe Non-Clinical Evaluation of the Potential for Delayed
Ventricular Repolarization (QT Interval Prolongation) by Human
Pharmaceuticals
Immunotoxicology Studies
S8 Immunotoxicity Studies for Human Pharmaceuticals
Joint Safety/Efficacy (Multidisciplinary) Topic
M3(R1) Non-Clinical Safety Studies for the Conduct of Human
Clinical Trials for Pharmaceuticals

31. Multidisciplinary Guidelines
M1: Medical Terminology
M2: Electronic Standards for transmission of
Regulatory Information ESTRI
M3: Timing of Pre-clinical Studies in relation to Clinical
Trials
M4: The Common Technical Document
M5: Data elements & standards for drug dictionaries
M6: SOPs for maintenance of ICH terminologies lists
action

32. What is CTD ?What is CTD ?
Common Technical Document
ICH M4 – deals with CTD
A harmonized format for a regulatory
dossier that is considered acceptable in
US, Japan Europe and Canada

33. What is CTD ?What is CTD ?
The CTD refers to an application format
The CTD is a prescribed organization of
the information required to be submitted.
Each regulatory authority retains the
ability to address its own regional specific
requirements for needed documentation.

34. Not
part
of
CTD
Module 1
Module 2
Module 3 Module 4 Module 5
Quality
Nonclinical
Study
Reports
Clinical
Study
Reports
Regional
Administrative
Information
Nonclinical
Summary
Clinical
Summary
Nonclinical
Overview
Clinical
Overview Quality
Overall
Summary
Organisation
of the CTD
CTD

35. Number of Number of
copies requiredcopies required

36. Module

1
Module 3 Module 4 Module 5
Quality
Nonclinical
Study
Reports
Clinical
Study
Reports
Regional
Administrative
Information
Nonclinical
Summary
Clinical
Summary
Nonclinical
Overview
Clinical
Overview
Quality
Overall
Summary
1.1 ToC of Mod 1 or
overall ToC, incl. Mod 1
2.3 2.6 2.7
2.4 2.5
CTD ToC (Mod 2,3,4,5)
CTD Introduction
4.1 ToC for
3.1 ToC for
Mod 3
2.1
2.2
Mod 4
5.1 ToC for
Mod 5
15
5
15
5151515
22
222

37. What is eCTD ?What is eCTD ?
Electronic format of the ICH Common
Technical Document
Moving towards a paperless submission
environment

38. eCTDeCTD
Electronic Common Technical Document
ICH has given specification
Electronic submission is easier and has
many advantages
The philosophy of eCTD is to use open
standards. Open standards including
proprietary standards which through their
widespread use can be considered can be
considered as de facto standard are
deemed to be appropriate in general
eCTD contains 5 modules

39. 5 modules of eCTD5 modules of eCTD
Module1- Administrative information &
Prescribing information – Regional specific
information
Module 2-Summaries
Module 3- Quality
Module 4- Non-clinical study reports
Module 5- Clinical study reports

40. Module 1Module 1
The CTD does not describe the module 1,
the regional administrative information
and prescribing information nor does it
describe documents that can be submitted
as amendments or variations to the initial
application

41. Module 2 SummariesModule 2 Summaries
Introduction
Overall quality summary
Non-clinical overview
Clinical overview
Non-clinical written and tabulated
summaries
Clinical summary

42. Module 3 - QualityModule 3 - Quality
Quality parameters of Drug substance
Quality parameters of Drug product
Reference standards
Container and closure system
Stability studies of Drug substance & Drug
product
Control of excipient
Control of Drug product

43. Module 4 – Non clinical study Module 4 – Non clinical study
reportsreports
Pharmacology
Pharmacodynamics
Safety pharmacology
Drug interactions
Pharmacokinetics
ADME
Toxicology
In-vitro and in-vivo evaluations
IVIVC
Carcinogenicity
Short term and long term studies
Reproductive and development toxicity
Literature references

44. Module 5 – Clinical dataModule 5 – Clinical data
Listing of all clinical
studies
Clinical study
reports
BA
BE
BA/BE
IVIVC
Bio-analytical
reports
PK
PD
PK/PD
Efficacy and safety
reports
Reports of PMS

45. Where are we today…Where are we today…
Working on becoming a standards based
organization
◦eCTD is just such a standard
Accepting IND, NDA, ANDA, BLA, DMF and
related submissions in eCTD format
Moving towards a paperless submission
environment

46. Where are we going…Where are we going…
Secure electronic transmission of eCTD
submission
◦Structured Product Labeling
◦Electronic submission in XML format

47. Electronic Submission GuidancesElectronic Submission Guidances
Using eCTD SpecificationsUsing eCTD Specifications
Providing Regulatory Submissions in
Electronic Format - Human
Pharmaceutical Product Applications and
Related Submissions
◦Includes NDA, ANDA, BLA, IND, DMF and
associated submissions
Preferred Format for Submissions

48. Electronic Submissions Using Electronic Submissions Using
eCTD SpecificationseCTD Specifications
Guidance Published August, 2003
eCTD Specifications
◦FDA eCTD Table of Contents Headings and
Hierarchy
◦FDA Module 1 Specification
◦FDA Modules 2 to 5 Specification
◦Study Tagging File Specification
Specifications Available On-Line
http://www.fda.gov/cder/regulatory/ersr/default.htm
Current eNDA/eANDA Guidances remain available
as an alternative to the eCTD for NDA and ANDA
only

49. Resources for IndustryResources for Industry
CTD and eCTD Subject Matter Experts
FDA is making EVS processing and review
tools available to industry
◦Download free from FDA web site
◦Tools provided on an as-is basis
◦No support from FDA will be provided
3
rd
party developers are creating tools to
support generation and validation of
submission prior to FDA submission

50. Just donJust don’t ask…’t ask…
No paper unless required for original
signatures
No Word files or file formats not specified
in the guidance
No electronic submissions or records sent
directly to a reviewer or project manager
No electronic desk copies

51. Traditional SignaturesTraditional Signatures
What are the
functions of a pen
and ink signature?

52. Functions of a Traditional SignatureFunctions of a Traditional Signature

¨ identification;
¨ authentication;
¨ declaration of will;
¨ authorization;
¨ safeguard against undue haste;
¨ non-repudiation of origin and receipt;
¨ notice of contents;
¨ integrity; and
¨ originality.
.

53. Non-cryptographic means of authenticating Non-cryptographic means of authenticating
identityidentity

PIN and a Password (shared secret);
a smart card;
a digitized signature; and
Biometrics.

54. cryptographic electronic cryptographic electronic
signaturesignature
PKI or Public Key
Infrastructure
Also known as
Digital Signatures
Highly Secure
.

55. Advantage of eCTDAdvantage of eCTD
Only module one has to be changed in
submitting to various countries
Module 2 to 5 remains same
Quicker submissions , quicker process and
there by quicker approvals

56. BenefitsBenefits
Our mission is to provide relief and hope for
millions of people around the world — And we
must do so as quickly as possible because …
The patient is waiting!The patient is waiting!

57. Conclusion Conclusion

58. THANKYOUTHANKYOU
PAVANI.GADUPUDI