ICH GUIDELINES
LECTURE 4
Purpose .participants ,process of harmonization ,brief overview of QSEM
with special emphasis on Q series guidelines ,ICH stability testing guidelines
PREPARED BY
Mrs. Ayushi Khurana
International council for harmonization /International
conference on harmonization
Harmonization ( Wishful to reality )
The realization that it was important to have an independent evaluation
of medicinal products before they are allowed on the market was
reached at different times in different region .
The realization was driven by tragedies one of the big tragedies
( Thalidomide tragedies in Europe in 1960s).
• In the 1990s ,harmonization around the world got going when the ICH
proved to be effective in bridging many of the gaps that existed in almost all
parts of the documentation required for NDA.
• The international conference on Harmonization of technical
requirements for the registration for pharmaceuticals for human use is a
tripartite initiative by (EU, JAPAN and USA) to harmonize the
regulatory guidelines in these three regions in order to reduce duplication
and redundancy in the development and registration of new drugs .
• Other cosponsors of this harmonization are :
EFPIA ( COSPONSOR) European federation of pharmaceutical industries association .
JPMA (COSPONSOR) Japan pharmaceutical manufacturer association
USFDA(COSPONSOR) United states of food and drug administration
IFPMA( ADVISER) International federation of pharmaceutical
manufacturers association.
WHO( OBSERVER) World health organization.
EFTA( ADVISOR) European free trade association.
In early years Three Objectives of ICH
1. To provide a forum between and among regulatory authorities and
the pharmaceutical industry for product registration in the EU ,US
and JAPAN.
2. To identify areas in which modifications in technical requirements or
greater mutual acceptance of research and development procedures
could to a more economical use of human, animal and material
resources without compromising safety .
3. To make recommendation on practical ways to achieve greater
harmonization in the interpretation and application of technical
guidelines and requirements for registration.
❑Progress is monitored by the committee at biannual conferences.
❑ICH has been highly successful in delivering on these promises going through
many stages (From 1991 -2003) .
❑The main focus of the ICH is on the studies and documentation needed for
submissions for market approval to the health authorities.
❑Finally the topic being addresses in the context of registration of drugs for human
use from the three main themes including :
❖QUALITY
❖SAFETY QSEM
❖EFFICACY.
❖MULTIDISCIPLINARY
• After this ICH moved to GMP with the development of global
manufacturing practice guide for active pharmaceutical ingredients.
• It took seven years and five attempts were made by national and
international bodies to arrive at harmonized document .But in the end none
of them was found good enough to be accepted by all the other parties.
• An ICH expert working group Q7 was established , consisting of 20
members which includes:
❖Members of ICH
❖IGPA ( INTERNATIONAL GENERIC PHARMACEUTICAL ALLIANCE) GENERIC
INDUSTRY members.
❖WMSI (World manufacturer self industry ) OTC INDUSTRY members
❖ Representative from Australia , China and India.
❖ WHO observers.
• What is the issue ????????????
After GMP was made but the question when it will be implementated
The solution of this , the inclusion of validation concepts that have
missing in the Q7.
Now the guidelines were categorized into four categories.
❖QUALITY
❖SAFETY
❖EFFICACY.
❖MULTIDISCIPLINARY
Categories of guidelines
Quality Guidelines(Q1-Q14)
Includes Stability studies,
Safety Guidelines(S1-S11)
thresholds for impurities testing, To uncover potential risk like
flexible approach for pharm. carcinogenicity, genotoxicity,
quality based GMP risk reprotoxicity
management
Efficacy Guidelines(E1-E19) Multidisciplinary Guidelines
Concerned with design, conduct, (M1 –M11)
safety & reporting of clinical trials Includes ICH medical terminology
Novel medicines derived from MedDRA, common tech. document
biotech processes, use of CTD, development of electronic
pharmacogenetics genomic tech. to standards for transfer of
produce targeted medicines regulatory information ESTRI
BRIEF OVERVIEW OF QSEM
• Q series: Quality Guidelines are
• Q1A-Q1F: Stability
• Q2- Analytical validation
• Q3A-Q3D – Impurities
• Q4A-Q4B- Pharmacopoeias
• Q5A-Q5E- Quality of Biotechnological products
• Q-6A-Q6B- Specifications
• Q7 – GMP
• Q8 Pharmaceutical Development
• Q9 Quality risk management
• Q10- Pharmaceutical Quality System
• Q11 Development & Manufacture of Drug substances
• Q12 Life cycle Management
• Q13 Continuous Manufacturing of Drug substances & drug products
• Q14 Analytical Procedure Development
Efficacy Guidelines E SERIES
• 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 trialsE11 –E11A Clinical Trials in pediatric population
• E12 Clinical Evaluation by Therapeutic category
• E14 Clinical Evaluation of QT (Wave, effect on Heart)
• E15 Definitions in Pharmacogenetics/ Pharmacogenomics
• E16 Qualification of Genomic Biomarkers
• E17 Multi Regional Clinical Trials
• E18 Genomic Sampling
• E19 Safety DATA Collection
Multidisciplinary guidelines M series
• M1 MedDRA Terminology
• M2 Electronic standards
• M3 Non clinical 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 based biowaivers
• M10 Bioanalytical Method development
• M11 Clinical electronic structured harmonized protocol
(CeSHarP)
Special emphasis on Q series
Q1 A R2 Stability testing of new drug SEP. 1994 Harmonize Intermediate
substances & products Rev. 2001 storage condition for Zone 1
(NDSP) Feb 2003 & II with long term condition
for Zone III & IV
recommended in Q1F
(Stability data package for
reg. applications in climatic
zones III & IV)
Climate Countries Def Storage conditions
zones Temp. Humidity
I Japan, UK, North Eur. Temperate 21 °C 45%
Canada, Russia, USA etc
II Japan South Eur USA etc Sub Trop 25°C 60%
Mediter.
III Iran Iraq Sudan etc Hot dry 30°C 35%
IV Brazil Ghana Indonesia Tropical
Nicaragua Philippines India 30°C 70%
Pak Bangladesh
• Variety of Env. factors- affecting quality of drug
• Stress testing: degradation products, intrinsic stability of
molecule
• Includes effect of temp in 10°C increment 50, 60 etc,
humidity 75% RH or greater, oxidation, photolysis
• Susceptibility to hydrolysis over wide pH range in solution/
suspension
• Photostability testing described in Q1B
• Frequency of testing: For long term studies: at least 12
months- every 3 month over first yr and every 6 months
over second yr & annually thereafter
• At accelerated storage condition minimum three time
points including initial and final time points (0,6,9,12
months) from a 12 month study
Storage conditions
• Test the thermal stability, sensitivity to moisture
• During storage, shipment, subsequent use
• General case:
• 3 primary batches- 12 month duration
• Long term: 12 M- 25°C±2°C/60%RH ±5% RH or
30°C±2°C/65%RH ±5% RH
• Intermediate: 6 months 30°C±2°C/65%RH ±5% RH
• Accelerated: 40°C±2°C/75%RH ±5% RH
• If long term studies show significant changes during
6 months- accelerated & intermediate studies to be
done
Storage conditions
• Storage in refrigerator
• Long term: 5°C±3°C 12 months
• Accelerated: 5°C±2°C/60% ±5 RH 6 months
• If significant change: b/w 3-6 months- accelerated
storage testing to be done
• In a freezer:
• Long term - 20°C±5°C 12 months
• For below -20°C treat on case by case basis
• Evaluation: if batch to batch variation is small,
combine data in one overall estimate
• Statement/ Labeling
• Storage statement on label- based on stability
evaluation
