1. DR. K. VENKATESWARA RAJU
ICH – GUIDELINES
ICH stands for “International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use”.
Which is international non-profit Association, which is unique in bringing
together the regulatory authorities and pharmaceutical industries.
Where European Union, Japan and the USA involve in scientific and technical
discussions of the testing procedures required to assess and ensure the safety,
quality and efficacy of medicines.
These are the three pillars on which the health of the patients depend.
ICH Guidelines accepted as law in several Countries to ensure and access the Q,
S, E of medicines but are only used as guidance for the U.S Food and Drug
Need to Harmonize
Many time-consuming and expensive test procedures, in order to market new
Over rising costs of health care making safe and efficacious new treatments
available to patients in need.
Divergence in technical requirements from country to country.
ORIGIN OF ICH
Harmonization of regulatory requirements was pioneered by the EU, Europe, in
the 1980s as the Europe move towards the development of single market.
The success achieved in Europe demonstrated that harmonization was feasible.
2. At the same time there were discussions between Europe, Japan and the US on
possibilities for harmonization.
The birth of ICH took place at a meeting in April 1990.
EFPIA (European federation of pharmaceutical industries’ associations).
MHLW (Ministry of health, Labor and welfare, Japan).
JPMA (Japan Pharmaceuticals manufacturers Association).
PhRMA (pharmaceutical research and manufacturers association).
Observers: WHO, TPP (Canada).
International federation of Pharmaceutical manufacturers association.
OBJECTIVES OF ICH
Promote public health by early availability of drug in the market.
Improve efficiency of new drug development, Reduce registration cost.
Less expensive drugs for patients.
Prevent the duplication of clinical trials in humans.
Minimize the animal use without compromising in safety, efficacy of the product.
Mutual acceptance of clinical data by regulatory authority.
Reducing testing duplication.
3. The guidelines of ICH are broadly categorized into four types.
Harmonisation achievements in the Quality area include pivotal milestones such
as the conduct of stability studies, defining relevant thresholds for impurities
testing and a more flexible approach to pharmaceutical quality based on Good
Manufacturing Practice (GMP) risk management.
ICH has produced a comprehensive set of safety Guidelines to uncover potential
risks like carcinogenicity, genotoxicity and reprotoxicity. A recent breakthrough
has been a non-clinical testing strategy for assessing the QT interval prolongation
liability: the single most important cause of drug withdrawals in recent years.
The work carried out by ICH under the Efficacy heading is concerned with the
design, conduct, safety and reporting of clinical trials. It also covers novel types
of medicines derived from biotechnological processes and the use of
pharmacogenetics/genomics techniques to produce better targeted medicines.
Those are the cross-cutting topics which do not fit uniquely into one of the
Quality, Safety and Efficacy categories. It includes the ICH medical terminology
(MedDRA), the Common Technical Document (CTD) and the development of
Electronic Standards for the Transfer of Regulatory Information (ESTRI).
4. QUALITY GUIDELINES
Q1A - Q1F: Stability
Q2: Analytical Validation
Q3A - Q3D: Impurities
Q4 - Q4B: Pharmacopoeias
Q5A - Q5E: Quality of Biotechnological Products
Q6A- Q6B: Specifications
Q7: Good Manufacturing Practice
Q8: Pharmaceutical Development
Q9: Quality Risk Management
Q10: Pharmaceutical Quality System
Q11: Development and Manufacture of Drug Substances
Q12: Lifecycle Management (DRAFT FORM)
Q13: Continuous Manufacturing of Drug Substances and Drug Products
Q14: Analytical Procedure Development (CONCEPT PAPER)
S1A - S1C: Carcinogenicity Studies
S2: Genotoxicity Studies
S3A - S3B: Toxicokinetic and Pharmacokinetics
S4: Toxicity Testing
S5: Reproductive Toxicology
S6: Biotechnological Products
S7A - S7B: Pharmacology Studies
S8: Immunotoxicology Studies
5. S9: Nonclinical Evaluation for Anticancer Pharmaceuticals
S10: Photo safety Evaluation
S11: Nonclinical Pediatric Safety
E1: Clinical Safety for Drugs used in Long-Term Treatment
E2A - E2F: Pharmacovigilance
E3: Clinical Study Reports
E4: Dose-Response Studies
E5: Ethnic Factors
E6: Good Clinical Practice
E7: Clinical Trials in Geriatric Population
E8: General Considerations for Clinical Trials
E9: Statistical Principles for Clinical Trials
E10: Choice of Control Group in Clinical Trials
E11 - E11A: Clinical Trials in Pediatric Population
E12: Clinical Evaluation by Therapeutic Category
E14: Clinical Evaluation of QT
E15: Definitions in Pharmacogenetics / Pharmacogenomics
E16: Qualification of genomic biomarkers
E17: Multi-Regional Clinical Trials
E18: Genomic Sampling
6. MULTIDISCIPLINARY GUIDELINES
M1: MedDRA Terminology
M2: Electronic Standards
M3: Nonclinical Safety Studies
M4: Common Technical Document.
M5: Data Elements and Standards for Drug Dictionaries
M6: Gene Therapy
M7: Mutagenic impurities
M8: Electronic Common Technical Document (eCTD)
M9: Biopharmaceutics Classification System-based Biowaivers
M10: Bioanalytical Method Validation
The Impact of ICH (Quality) on industry:
1. The ICH guidelines in the quality area have provided recommendations in two of
the key areas that define bulk drug and drug product quality- stability data and
impurities- and led to significant reduction in duplicate testing.
2. Prior to there was no harmonized approach to the data requirements in these
areas. With stability for example, it was typical to run studies at “room
temperature” as defined by the company concerned, and appropriate to the
3. There was also no humidity control. This resulted in registrations in different
regions requiring new stability data if the climatic zone was different to that
where the original study had been conducted.
7. 4. ICH harmonization provided standard sets of conditions taking account of the
climatic zones in each of the three regions.
5. This means that the information on stability generated in any one of the three
regions is mutually acceptable in the other two areas, provided it meets the
requirements of the guideline. This removed the duplicate testing.
6. The impurities guidelines [Impurities in New Drug Substances (Q3A), Impurities
in New Drug Products (Q3B), and Impurities: Guideline for Residual Solvents
(Q3C)] also served, as with the stability guidelines, to provide scientific
agreement on the recording and reporting of impurity levels.
7. Guidelines were also provided on how changes in impurity profile over the course
of a development program should be managed. The result of this is that it should
be possible to determine a single specification for any drug substance or product
that is acceptable across the three ICH regions. This makes the supply chain far
simpler, and minimizes supply error.
8. The ICH has also produced a parallel set of guidelines covering the specification
issues associated with biotechnological products. Standardization through the
guidelines has been a very positive step for the biotechnology industry, and has
certainly had a significant favorable impact on both development times and
9. Duplication of research was reduced related to the stability testing, impurity
ICH STABILITY GUIDELINES
8. Definitions and storage
conditions for four climatic
Storage conditions for general
Type of study Storage Condition Minimum time period covered
by data at submission
Long term 30ºC ± 2ºC and 65%RH ± 5%RH 12 Months
Accelerated 40ºC ± 2ºC and 75%RH ± 5%RH 6 Months
Climatic Zone Definition Storage Condition Examples
I Temperate climate 21ºC ± 2ºC and
45%RH ± 5%RH
II Mediterranean and
25ºC ± 2ºC and
60%RH ± 5%RH
Southern Europe, US,
III Hot dry climate 30ºC ± 2ºC and
35%RH ± 5%RH
IV Hot and humid
30ºC ± 2ºC and
75%RH ± 5%RH
Central Africa, south
9. Common technical document
Common technical document (CTD) is a format that was created by the ICH in an
attempt to harmonize the format of a drug approval’s applications in all 3 ICH
regions , i.e. the USA, Europe, and japan. The CTD was agreed upon in November
2000, in san Diego, California, the USA.
CTD is a common format/ template to provide the information to the drug regulatory
authorities in the 3 ICH regions. It is not a “single” dossier, with a “single” content
since legal requirements and applicant preferences differ in the 3 different ICH
The CTD as defined by the ich m4 expert working group(EWG)does not cover the
full submission that is to be made in a region.it describes only module 2 to 5, which
are common across all regions. The CTD does not describe the content of 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
The CTD is a set of specifications for the submission of regulatory data in the
application for obtaining market approval for pharmaceuticals. the format of the
CTD is not to be confused with its content or submission type, rather ,it is the means
by which information in a submission is organized.
Specifications for the organization of content of CTD
For modules 2-5, the ICH specifies the organization and content for CTD. For
module 1, the ICH specifies the regional sections, the specific regulatory authority
(i.e. FDA, Singapore, health Canada and india) specifies the organization and
content for CTD, therefore regional section content may vary between different ICH
Objectives of ICH behind CTD
10. 1. To present a well-structured common format for the preparation for
approvals applications which will be submitted to regulatory authorities.
2. To significantly reduce the time and resources needed to compile
applications for registration of human pharmaceuticals and ease the
preparation of electronic submissions.
3. To facilitate the regulatory reviews and communication with the applicant
by using a standard document of common elements.
4. To prevent unnecessary duplication of work.
Benefits of the CTD
1.Complete, well organized submissions
2. More predictable format
3.More consistent reviews
4.Easier analysis across applications
5.Eaiser exchange of information
6.Facilitates electronic submissions
11. ORGANIZATION OF THE COMMON TECHNICAL DOCUMENT
The common technical document is organized in to five modules
OBJECTIVES OF CTD GUIDELINE
This guideline is intended to provide recommendations on how to use stability
data generated in accordance with the principles detailed in the ICH guideline
Q1A(R) stability testing of new drug substances and products.
A regional specific module containing administrative information,
and is unique to each regulatory authority.
Contains overviews, written summaries and tabulated summaries
of the data contained in modules3,4 and 5
Contains quality data relating to the drug substances and drug
Contains non clinical data
Contains clinical date
12. Stability protocol and report
4.Literature and supporting data
5.Stability-indicating analytical method
9.Other requirements (Post -approval commitments)