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1. ICH
Purpose, participants, process of
harmonization, Brief overview of QSEM,
with special emphasis on Q-series
guidelines, ICH stability testing guidelines
INTERNATIONAL COUNCIL FOR
HARMONIZATION

2. ICH Guidelines : Inception 1990
 International council for harmonization, earlier
Conference
 Technical requirement for pharmaceuticals for
human use
 Step to bring regulatory authorities &
Pharmaceutical Industry to discuss scientific &
technical aspects of drug registration
 Mission of ICH: To achieve greater harmonization
worldwide to ensure safe, effective, high quality
medicines are developed/registered in most
resource & effective manner

3. History
 In 1980s Europen Union began harmonising
regulatory requirements
 In 1989s (European, Japan and United state)
began creating plan for harmonisation.
 In April 1990 ICH was created had initial
objectives of coordinating the regulatory activities.

4. PURPOSE OF ICH GUIDELINES
 Registration & maintenance of Pharmaceutical
product registration
 To have dialogues on scientific issues b/w
regulatory authorities & Pharmaceutical Industry
for harmonization of technical requirements of
Pharm. product
 Contribute to public health
 Monitor & update harmonized technical
requirements, leads to mutual acceptance of R& D
data
 To avoid various future requirements through
harmonization of selected topics
 Facilitate adoption of new or improved technical
R&D approaches, replacing or updating current

5.  Implementation & integration of common
standards by dissemination of the
communication of information about and
coordination of training on harmonized
guidelines & their use
 To develop policy for ICH medical dictionary for
regulatory activities terminology (MedDRA)-
share regulatory information internationally for
medicinal products
 Process of harmonization: 4 categories
 Formal ICH procedure
 Q & A procedure
 Revision procedure
 Maintenance procedure

7. Participants of ICH
 ICH Assembly
 ICH management comitte
 MedDRA mangament comittee
 ICH Secretariate

8. ICH Members
 Regulatory members
• EC, Europe
• FDA, United States
• MHLW/PMDA, Japan
• Health Canada, Canada
• Swissmedic, Switzerland
• ANVISA, Brazil
• COFEPRIS, Mexico
• HSA, Singapore
• MFDS, Republic of Korea

9.  Industrial member
 EFPIA
 JPMA
 PhRMA
 BIO
 IGBA
 Standing observer
 IFPMA
 WHO

10. 4 Categories of ICH topics
Quality Guidelines
Includes Stability studies,
thresholds for impurities testing,
flexible approach for pharm.
quality based GMP risk
management
Safety Guidelines
To uncover potential risk like
carcinogenicity, genotoxicity,
reprotoxicity
Efficacy Guidelines
Concerned with design, conduct,
safety & reporting of clinical trials
Novel medicines derived from
biotech processes, use of
pharmacogenetics genomic tech.
to produce targeted medicines
Multidisciplinary Guidelines
Includes ICH medical terminology
MedDRA, common tech.
document CTD, development of
electronic standards for transfer
of regulatory information ESTRI

11. 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

12.  S1A- S1C- Carcinogenicity studies
 S3A-S3B- Toxicokinetics & Pharmacokinetics
 S4- Toxicity testing
 S5 Reproductive testing
 S6 Biotechnological Product
 S7A-S7B- Pharmacology studies
 S8- Immunotoxicology studies
 S9 Non clinical evaluation of anticancer
pharmaceuticals
 S10 Photosafety
 S11 Non clinical pediatric safety
Safety Guidelines S Series

13. 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 trials

14. Efficacy Guidelines E SERIES
 E11 –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

15. 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

19. Special emphasis on Q series
Q1 A R2 Stability testing of new drug
substances & products
(NDSP)
SEP. 1994
Rev. 2001
Feb 2003
Harmonize Intermediate
storage condition for Zone 1
& II with long term condition
for Zone III & IV
recommended in Q1F
(Stability data package for
reg. applications in climatic
zones III & IV)
Climate
zones
Countries Def Storage conditions
Temp. Humidity

21.  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

22. 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

24. Q1B- Photostability (PS) testing of NDSP
 Source of light
 During testing- control of temp. & maintain dark env.
 Option 1: D65/ID 65 emission standard- artificial day light
fluorescent lamp combined with visible , UV, xenon or metal
halide lamp.
 ISO 10977 (1993)- D65- internationally recognized standard
for outdoor daylight
 Option 2: same sample to be exposed to cool white
fluorescent lamp in ISO 10977 and near UV lamp.
 Procedure: expose samples to light of 1.2million lux hrs &
emits near UV energy of 200 watt hr/sqmt
 Compare drug subst. & drug product
 For confirmation- samples exposed to validated chemical
actinometric system/ calibrated radiometers/lux meters to
monitor duration of exposure
 Dark control samples wrapped in aluminium foil kept beside
authentic sample

25. Decision on results
 For drug substances:
 Results of confirmatory studies to indicate
precautionary measures to be taken during
manufacturing so that the degradation of dosage form
is avoided during mfg.
 To ensure that drg remains within limits at the time of
its use
 For dosage forms:
 Special labeling or packaging depending on
degradation of dosage form.
 Ensure that formulation should comply with the
specifications for its quality/safety and therapeutic
efficacy during shelf life

26. Q1C- Stability testing for new dosage forms
 Issued on October 27th 1993
 It is annexure to ICH parent stability guideline
 Tells what is to be submitted in support of stability of
new dosage forms by the owner of original application
after original submission of NDSP
 New dosage form? It is the drug product which is
different from existing drug product but contains same
drug substances as in its existing product approved by
Regulatory Authorities
 Ex: Product of different routes of administration eg. Oral
to parenteral
 New specific functionality/delivery systems eg.
Immediate release tablet to modified release tablet
 Different dosage forms of same administration routes
eg. Capsule, tablet, solution to suspension

27. Q1D Bracketing and matrixing designs for stability
testing of NDSP
 Full study design : samples for every combination of all design
factors are tested at all time points
 Bracketing : design of a stability schedule so that only samples
on extremes of certain design factors eg. Strength, container size
or fill are tested at all time points as in full design (ex: 15ml-500ml
containers extreme)
 Design assumes that the stability of any intermediate levels is
represented by the stability of the extremes tested
 Design factors are variables: strength, container size/fill to be
evaluated in a study design for their effect on product stability
 Matrixing: is the design of a stability schedule such that a
selected subset of the total number of possible samples for all
factor combination would be tested at a specified time point
 At a subsequent time point another subset for all factor
combination would be tested
 Design assumes that the stability of each subset of samples
tested represents the stability of all samples at a given time point

28. Q1E Evaluation of stability data
 Tells how to use the stability data generated during
stability testing
 How to use Stability Data to be submitted in registration
application for new drug entity
 Guideline Recommends on establishing retest periods,
shelf lives of drug storage at or below RT
 Covers stability studies using single/multi factor
designs and full or reduced designs
 Purpose of Stability study: To establish retest period
or shelf life and label storage instructions
 Stability information should include data on physical,
chemical, biological and microbiological tests and also
special to dosage forms like dissolution rate for solid
dosage forms

29. Q1F : Stability Data package for registration
applications in climatic zones III and IV
 It is annexure to parent guideline Q1A (R): Stability testing of
NDSP
 Recommends long term storage condition for stability testing
of NDSP for registering application in climatic zones III and
IV
 Following common guidelines are considered to any territory
in world
 Stress testing
 Selection of batches
 Container closure system
 Specification
 Testing frequency
 Storage conditions for drug substance or product in a
refrigerator
 Storage conditions for drug subs or product in a freezer
 Stability commitment

30.  General case as per parent guideline: long term and
accelerated storage conditions for climatic zone III and
IV
 No intermediate storage conditions are recommended
in Zone III and IV
 For aqueous based drug products packaged in semi
permeable containers as per parent guidelines
Study Storage Condition Minimum time period covered by
data at submission
Long term 30°C±2°C/65%RH±5%RH 12 months
Accelerated 40°C±2°C/75%RH±5%RH 6 months
Study Storage Condition Minimum time period
covered by data at
submission
Long term 30°C±2°C/35%RH±5%RH 12 months
Accelerated 40°C±2°C/25%RH±5%RH 6 months

31. Q2 ANALYTICAL VALIDATION
 Done to demonstrate that NS, DP are suitable for
intended purpose
 Should describe each step important to perform each
analytical test
 Sample, reference standard, reagent preparation, use of
apparatus, calibration curve, formula for calculations
 Common analytical procedures:
 Identification tests, Quantitative tests for impurities,
Limit test, Quantitative tests of the active moiety in
samples
 Typical validation characteristics are:
 Accuracy, Precision, Repeatability, Intermediate
precision, specificity, detection limit, quantitation limit,

32. Q3A-Q3D impurities
 Impurities in New drug substances have 02 aspects
 Chemistry aspects: classification and identification of
impurities, report generation, listing of impurities in
specifications, brief discussion of analytical procedures
 Safety aspects: specific guidelines for those impurities
which were not present or in low levels in batches of
NDS used in safety and clinical studies

33. Classification of Impurities
Organic impurities Inorganic
Residual
solvents
Starting
materials
By products
Degradation
products
Reagents,
ligands,
catalysts
During storage, Mfg.,
volatile non-vol.
identified/non Reagents,
ligands,
catalysts
Heavy
metals/residual
metals
Inorganic salts
Filter
aids/charcoal/
others
Results from Mfg.
process/ usually known
& identified
Inorganic/organic
Of known toxicity
Q3C guidelines

34. Other impurity guidelines
Q3 A (R2) Impurities in New Drug Substances
Q3B (R2) Impurities in New Drug Products
Q3C (R7) Impurities : Guidelines in Residual solvents
Q3 D Guideline for elemental impurities
Q3 D (R1) Revision of Q3D Cadmium inhalation
Q3D (R2) Revision of Q3D for cutaneous & transdermal products
Q3D Training implementation of guideline for elemental impurities

35. Q4-Q4B PHARMACOPOEIAS
 Q4 Pharmacopoeias
 Q4 A Pharmacopoeial Harmonization
 Q4 B- Evaluation of recommendation of
pharmacopoeial texts for use in the ICH regions
 Q4B- Annex. 1R1 Residue on ignition/sulphated ash
 Q4B- Annex. 2R1- Test for extractable volume of
parenteral preparations
 Q4 B Annex. 3R1- Test for particulate contamination:
Sub visible particles
 Q4B Annex. 4AR1: microbiological examination of non
sterile products: Microbial enumeration tests
 Q4B Annex. 4BR1: microbiological examination of non
sterile products: Tests for specified micro organisms

36. Q4-Q4B PHARMACOPOEIAS
 Q4B- Annex. 4CR1 microbiological examination of non
sterile products: Acceptance criterion for pharmaceutical
preparations & substances for pharmaceutical use
 Q4B- Annex. 5R1-Disintegration test
 Q4 B Annex. 6- Uniformity of dosage units
 Q4B Annex. 7R2:Dissolution test
 Q4B Annex. 8R1: Sterility Test
 Q4B Annex. 9R1: Tablet friability
 Q4B Annex. 10R1: Polyacrylamide Gel electrophoresis
 Q4B Annex. 11: Capillary electrophoresis
 Q4B Annex. 12: Analytical sieving
 Q4B Annex. 13: Bulk density & tapped density of powders
 Q4B Annex. 14: Bacterial endotoxins test
 Q4B FAQs Frequently asked questions

37. Q5 A-Q5E: Quality of Biotechnological Products
 Q5A (R1): Viral safety evaluation of Biotechnological
products derived from cell lines of human of animal
origin
 Q5B Analysis of the expression construct in cells used
for production of r-DNA derived protein products
 Q5C Stability testing of biotechnological / Biological
products
 Q5 D Derivation & characterization of cell substrates
used for production of biotechnological / biological
products
 Q5E Comparability of biotechnological / biological
products subject to changes in their manufacturing
process

38. Q6 A-Q6B: Specifications
 Q6A Specifications: Test procedures & acceptance
criteria for NDSP, Chemical substances
 Q6B Specifications: Test procedures and acceptance
criteria for biotechnological / biological products
Q7: GMP: Outlines the manufacturing of API
Q8: Pharmaceutical Development
 Aim is to design a quality product & its mfg. process
 Quality should be built in by design
 Information & knowledge gained from pharmaceutical
development studies & mfg. experience provides
scientific understanding to support establishment of the
design space.

39. Q9: Quality Risk Management
Process for assessment, control, communication, review of
risks to quality of drug across life cycle of product
Principles: Based on scientific knowledge & links to patient
 Level of effort, formality and documentation of QRM
 Coordinate, facilitate and improve sciences based decision
making with respect to risk
Steps to initiate and plan QRM:
 Define problem, risk
 Assemble background information or data on potential
hazard, harm, human health impact
 Identify a leader and resources
 Specify timeline, deliverables and appropriate level of
decision making for risk management process

40. Q9: Quality Risk Management
 Risk Assessment
 Consists of identification of hazards & analysis &
evaluation risks
Quality Risk Management:
 Systemic use of information to identify hazards
 Information includes historic data, theoretical analysis,
informed opinions, concerns to stakeholders
Risk control
 Includes decision making to reduce or accept risks
 Purpose is to reduce risk to an acceptable level

41. Q10: Pharmaceutical Quality System
 Management system to direct and control Pharm.
company related to quality
 ICH Q10 based on ISO 9000:2005
 Regional GMP requirements, ISO standards & ICH Q7
regional GMP req., ICH Q7 guideline GMP guide for
API, ISO quality management system guideliness form
foundation of ICH Q10
 Continuous improvement across entire product lifecycle

42. Q11: Development and manufacture of drug
substances
 Addresses the aspects of Development and
manufacture including steps designed to reduce the
impurities
 Also provides clarification on ICH on Q8, Q9, Q10.
 Traditional approach: set points & operating ranges
for process parameters.
 Process reproducibility & testing to meet standard
goal
 Enhanced approach: Risk management & scientific
knowledge to identify process parameters, unit
operations impacting the critical quality attributes
(CQAs)

43. Q13: Continuous manufacturing (CM) of Drug
substances and Drug product
 CM improves efficiency, expedition, flexibility
 But lack of regulatory guidelines can make implementation,
regulatory approval, lifecycle management challenging,
particularly for products for commercialization on
International basis
 ICH guideline facilitate International harmonization
 Reduces barrier to adoption of CM technology
 Revised ICH Q2 R1
 New guidelines for harmonizing the scientific approaches of
analytical procedure development
 Improves regulatory communication b/w Industry & regulators
 Facilitates efficiency, sound scientific and risk based
approval.
 Include validation principles covering use of spectroscopic or
spectrometry data (NMR, Raman, MS)
Q14: Analytical Procedure Development