QUALITY ASSURANCE (B.

PHARM 3RD YEAR)

ICH GUIDELINES
The International Council for Harmonization of Technical Requirements for Pharmaceuticals for
Human Use (ICH) collaborates with regulatory authorities and the pharmaceutical industry to create
guidelines for safe, effective, and high-quality medicines.
1. Collaborative Approach: ICH brings together regulatory authorities and the pharmaceutical
industry to discuss scientific and technical aspects of pharmaceuticals.
2. Creation of Guidelines: The council develops guidelines to ensure safe, effective, and high-
quality medicines.
3. Global Adaptation: Established in 1990, ICH adapts to global developments in the
pharmaceutical sector.
4. Widespread Adoption: ICH guidelines are increasingly adopted by regulatory bodies worldwide.
5. Expansion: Since its restructuring in 2015, ICH has grown to include 23 Members and 38
Observers.
6. Mission: To harmonize standards for medicine development, registration, and maintenance
efficiently and effectively.
WHY WE NEED ICH GUIDELINES
1. Harmonisation for Better Health: ICH aims to harmonize technical requirements for
pharmaceuticals to ensure high-quality, safe, and effective medicines.
2. Efficient Guidelines Development: Achieves harmonisation through the creation of ICH
Guidelines via scientific consensus with regulatory and industry experts.
3. Commitment to Implementation: Success depends on the commitment of ICH regulators to
implement the final guidelines.
Key Articles of Association:
1. Recommendations: Achieve greater harmonisation in the interpretation and application of
technical guidelines for pharmaceutical registration and maintenance.
2. Constructive Dialogue: Maintain a environment for scientific discussions between regulatory
authorities and the pharmaceutical industry.
3. Public Health Contribution: Protect public health from an international perspective.
4. Updating Requirements: Monitor and update harmonised technical requirements for greater
mutual acceptance of research and development data.
5. Avoid Divergent Requirements: Harmonise selected topics to avoid divergent future
requirements due to therapeutic advances and new technologies.
6. Adoption of New Approaches: Facilitate the adoption of new or improved technical research
and development approaches.
7. Implementation and Training: Encourage the implementation and integration of common
standards through dissemination, communication, and coordination of training on harmonised
guidelines.

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8. MedDRA Policy: Develop policy for the ICH Medical Dictionary for Regulatory Activities
Terminology (MedDRA) and ensure its scientific and technical maintenance, development, and
dissemination as a standardised dictionary.

History
New Identity: Formerly known as the International Conference on Harmonisation, ICH was rebranded
and held its inaugural Assembly meetings on 23 October 2015.
Legal Entity: ICH was established as an international association, a legal entity under Swiss law.
Track Record: This step built upon a 25-year track record of successfully delivering harmonised
guidelines for global pharmaceutical development and regulation.
Need for Harmonisation: Reflects a long-standing recognition of the necessity to harmonise technical
requirements for pharmaceuticals.
The Need to Harmonise
1. Importance of Evaluation: Realization of independent evaluation for medicinal products
emerged at different times, often driven by tragedies like the thalidomide disaster in Europe.
2. Regulatory Evolution: The 1960s and 1970s saw a surge in laws and guidelines for new
medicinal products due to rising healthcare costs and global market expansion.
3. Harmonisation Necessity: Diverse technical requirements led to time-consuming and costly
duplication of tests, pushing for regulation harmonisation.
Initiation of ICH
1. Pioneering Harmonisation: The European Community (EC) started harmonisation efforts in
the 1980s, demonstrating feasibility.
2. Global Discussions: Europe, Japan, and the US discussed harmonisation at the WHO
Conference in 1989, leading to ICH's conception.
3. First Meeting: ICH was officially founded in April 1990 in Brussels, with the first Steering
Committee meeting defining harmonisation topics: Safety, Quality, and Efficacy.
Evolution of ICH
1. 1990s: Significant progress on guidelines for Safety, Quality, and Efficacy; multidisciplinary
topics like MedDRA and the CTD.
2. 2000s: Focus on expanding communication and implementation of guidelines beyond ICH
regions.
3. 2015 Reforms: Organisational changes to increase international outreach, governance
structure changes, and establishment as a legal entity for stability.
4. Current Focus: Extending harmonisation benefits globally, with the Assembly as the
governing body promoting active involvement from regulatory authorities and industry
organizations.

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 QUALITY ASSURANCE (B. PHARM 3RD YEAR)

MEMBERS
Founding Regulatory Members
1. EC, Europe
2. FDA, United States
3. MHLW/PMDA, Japan
Founding Industry Members
1. EFPIA
2. JPMA
3. PhRMA
Standing Regulatory Members
1. Health Canada, Canada
2. Swiss medic, Switzerland
3. Regulatory Members
4. ANVISA, Brazil
5. ANMAT, Argentina
6. COFEPRIS, Mexico
7. EDA, Egypt
8. HSA, Singapore
9. JFDA, Jordan
10. MFDS, Republic of Korea
11. MHRA, UK
12. NMPA, China
13. SFDA, Saudi Arabia
14. TFDA, Chinese Taipei
15. TITCK, Türkiye
Industry Members
1. BIO
2. Global Self-Care Federation
3. IGBA

OBSERVERS
Standing Observers
• IFPMA
• WHO
Legislative or Administrative Authorities
1. AEC, Azerbaijan
2. ANPP, Algeria
3. CDSCO, India
4. CECMED, Cuba
5. CPED, Israel
6. CPPS, Uzbekistan
7. DIGEMID, Peru
8. DPM, Tunisia
9. Indonesian FDA, Indonesia

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10. INVIMA, Colombia

11. MMDA, Moldova
12. MOPH, Lebanon
13. NAFDAC, Nigeria
14. National Center, Kazakhstan
15. NPRA, Malaysia
16. NRA, Iran
17. PPBHK, Hong Kong, China
18. Roszdravnadzor, Russia
19. SAHPRA, South Africa
20. SCDMTE, Armenia
21. SECMOH, Ukraine
22. Thai FDA, Thailand
23. TGA, Australia
Regional Harmonization Initiatives (RHIs)
1. APEC
2. ASEAN
3. EAC
4. GHC
5. PANDRH
6. SADC
International Organization regulated or affected by ICH Guideline(s)
1. Gates Foundation
2. CIOMS
3. EDQM
4. IPEC
5. PIC/S
6. USP

Process of Harmonization
ICH harmonisation activities fall into 4 categories: Formal ICH Procedure, Q&A Procedure, Revision
Procedure and Maintenance Procedure, depending on the activity to be undertaken.

1. Formal ICH Procedure

2. Questions & Answers Procedure
3. Revision Procedure
4. Maintenance Procedure

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 QUALITY ASSURANCE (B. PHARM 3RD YEAR)

1. Formal ICH Procedure

Step 1 Step 2 Step 3 Step 4 Step 5

a. ICH
Parties
consensus
on
Technical Adoption
Consensus Regulatory
Document of an ICH
building - consultatio Implement
Harmonise
Technical n and ation
b. Draft d
Document Discussion
Guideline Guideline
adoption
by
Regulators

2. Questions & Answers Procedure

✓ Purpose: Provides additional guidance for interpreting ICH harmonised Guidelines.

✓ Stakeholder Questions: Driven by questions/issues from stakeholders, often submitted via
the ICH website.
✓ Concept Paper: Procedure starts with the ICH Assembly endorsing a Concept Paper.
✓ Business Plan: Required for major implementation activities.
✓ Implementation Working Group (IWG): Formed to develop Q&A documents.
✓ Recommendation: IWG recommends if the draft Q&A should be published for consultation
(Step 2b) or as a final document (Step 4).

3. Revision Procedure

✓ Purpose: Used when the scientific/technical content of an existing guideline is outdated or

when new information needs to be added without amending the existing guideline.
✓ Forms of Addition: New information can be added as an Addendum or an Annex.
✓ Similarity to Formal Procedure: Follows the 5 ICH Steps, with the final outcome being a
revised guideline instead of a new one.
✓ Initiation: Starts with the endorsement of a Concept Paper by the ICH Assembly.
✓ No Business Plan Required: A Business Plan is not necessary for revisions.
✓ Expert Working Group (EWG): Established to handle the revision.
✓ Designation: Revised guidelines are designated with R1, R2, R3, etc., for each revision.
✓ Addition of Addendum/Annex: Upon reaching Step 4, the Addendum or Annex is added to
the existing guideline, resulting in a revised guideline.

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4. Maintenance Procedure

1. Applicability: Used for Q3C, Q3D, M7, Q4B, S5 Guidelines, and M2 Recommendations.
2. Purpose: Update guidelines with new information or address outdated content.

Specific Procedures

1. Q3C/Q3D Guidelines: Propose PDE for new/revised solvent/elemental impurities.

2. M7 Guideline: Propose AIs/PDE for new/revised DNA reactive impurities.
3. Q4B Annexes: Triggered by PDG's sign-off of a revised text.
4. S5 Annexes: Revise modifications of in vivo studies, reference compound list, and alternative
assays.
5. M2 Recommendations: Flexible changes without the formal ICH step process; approved by
EWG and ICH Assembly.

The ICH topics are divided into the four categories below and ICH topic codes are assigned according
to these categories.

1. Quality Guidelines

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.

2. Safety Guidelines

ICH has produced a comprehensive set of safety Guidelines to uncover

potential risks like carcinogenicity, genotoxicity and repro-toxicity
(reproductive system). 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.

3. Efficacy Guidelines

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.

4. Multidisciplinary Guidelines

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).

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Q series guidelines
1. Stability (Q1A-Q1F, Q1 EWG):
Focuses on how to test and evaluate the stability of drug substances and products over time under
various conditions.
Includes photostability, stability for new dosage forms, bracketing and matrixing designs, evaluation
of data, and specific requirements for different climatic zones.
2. Analytical Validation (Q2, Q14):
Deals with the validation of analytical procedures used to test drug substances and products, ensuring
reliability and accuracy.
Covers analytical procedure development.
3. Impurities (Q3A-Q3E):
Sets guidelines for identifying and controlling impurities in drug substances and products, including
residual solvents and elemental impurities.
Also covers extractables and leachables (substances that can contaminate a drug product during
storage, use, or application).
4. Pharmacopoeias (Q4A-Q4B):
Aims to harmonize pharmacopoeial requirements across different regions.
Evaluates and recommends pharmacopoeial texts for use in ICH regions, covering various analytical
test procedures.
5. Quality of Biotechnological Products (Q5A-Q5E):
Provides guidance on the quality aspects of biotechnological and biological products, including viral
safety, analysis of expression constructs, stability testing, cell substrate characterization, and
comparability.
6. Specifications (Q6A-Q6B, Q6(R1) EWG):
Defines test procedures and acceptance criteria for new drug substances and products, both chemical
and biotechnological/biological.
7. Good Manufacturing Practice (GMP) (Q7):
Sets GMP guidelines for the manufacture of active pharmaceutical ingredients (APIs).
8. Pharmaceutical Development (Q8):
Focuses on the scientific and quality risk management approaches to pharmaceutical development.
9. Quality Risk Management (Q9):
Provides principles and guidelines for quality risk management.
10. Pharmaceutical Quality System (Q10):
Describes a model for a pharmaceutical quality system.
11. Development and Manufacture of Drug Substances (Q11):
Guidance on the development and manufacture of drug substances.
12. Lifecycle Management (Q12):
Technical and regulatory considerations for pharmaceutical product lifecycle management.

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 QUALITY ASSURANCE (B. PHARM 3RD YEAR)

13. Continuous Manufacturing (Q13):

Guidance on continuous manufacturing of drug substances and drug products.
14. Analytical Procedure Development (Q14):
Guidance on the development of analytical procedures.

ICH Q1A guideline, "Stability Testing of New Drug

Substances and Products."
1. Introduction:
• Objectives:
✓ To define the stability data package needed for registration applications in the EC,
Japan, and the US.
✓ To provide a flexible framework for various practical situations.
• Scope:
o Applies to new molecular entities and associated drug products.
o Does not cover abbreviated applications, variations, clinical trial applications, etc.
• General Principles:
➢ Stability testing assesses how drug quality changes over time due to environmental
factors.
➢ Establishes re-test periods (drug substance) or shelf life (drug product) and storage
conditions.
➢ Uses climatic data to define testing conditions, focusing on climatic zones I and II.
➢ Promotes mutual acceptance of stability data across the three regions.
2. Guidelines:
• 2.1. Drug Substance:
o Stress Testing:
▪ Identifies likely degradation products and pathways.
▪ Includes temperature, humidity, oxidation, photolysis, and pH sensitivity
testing.
▪ Photostability testing is integral (refer to ICH Q1B).
o Selection of Batches:
▪ At least three primary batches, manufactured at pilot scale, representing
production batches.
o Container Closure System:
▪ Use the proposed storage and distribution packaging.
o Specification:
▪ Tests attributes susceptible to change, including physical, chemical, biological,
and microbiological.

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 QUALITY ASSURANCE (B. PHARM 3RD YEAR)

▪ Use validated stability-indicating analytical procedures.

o Testing Frequency:
▪ Long term: Frequent testing initially, then less frequent as time progresses.
▪ Accelerated: Minimum of three time points.
▪ Intermediate: Minimum of four time points (when required).
o Storage Conditions:
▪ Long term, accelerated, and intermediate conditions are specified for general
cases, refrigerated, and frozen storage.
▪ "Significant change" is defined as failure to meet specifications.
o Stability Commitment:
▪ Commitment to continue stability studies post-approval if long-term data
doesn't cover the proposed re-test period.
o Evaluation:
▪ Establish a re-test period based on data from at least three batches.
▪ Statistical analysis may be required.
▪ Extrapolation of data is possible with justification.
o Statements/Labeling:
▪ Storage statements and re-test dates should be based on stability data.
• 2.2. Drug Product:
o General:
▪ Design based on drug substance stability and clinical formulation studies.
o Photostability Testing:
▪ Conducted on at least one primary batch (refer to ICH Q1B).
o Selection of Batches:
▪ At least three primary batches, in the proposed marketing packaging.
o Container Closure System:
▪ Use the proposed marketing container closure system.
o Specification:
▪ Tests attributes susceptible to change, including physical, chemical, biological,
microbiological, preservative content, and functionality.
▪ Shelf-life acceptance criteria should be derived from stability data.
o Testing Frequency:
▪ Similar to drug substance, with long term, accelerated, and intermediate
conditions.
▪ Reduced designs (matrixing/bracketing) are possible.

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o Storage Conditions:
▪ Long term, accelerated, and intermediate conditions are specified for general
cases, impermeable containers, semi-permeable containers, refrigerated, and
frozen storage.
▪ "Significant change" is defined with more product specific parameters.
o Stability Commitment:
▪ Same general principles as drug substance.
o Evaluation:
▪ Same general principals as drug substance.
o Statements/Labeling:
▪ Storage statements and shelf life should be based on stability data.
2.3. Evaluation (Drug Product - Continued):
• Statistical Analysis:
✓ For quantitative attributes changing with time, determine the time when the 95% one-
sided confidence limit of the mean curve intersects the acceptance criterion.
✓ If batch-to-batch variability is low, combine data using statistical tests (e.g., p-values >
0.25 for slope and intercept comparison).
✓ If combining is inappropriate, base shelf life on the minimum time a batch stays within
acceptance criteria.
✓ Transform data for linear regression if needed (linear, quadratic, or cubic functions).
✓ Test the goodness of fit of the data to the assumed degradation model.
✓ Limited extrapolation of long-term data is possible with justification (degradation
mechanisms, accelerated testing, model fit, batch size, supporting data).
✓ Evaluate assay, degradation products, and other relevant attributes.
✓ Mass balance should be reviewed.
• Key Considerations:
▪ The evaluation must consider not only the assay, but also levels of degradation products
and other attributes.
▪ Mass balance data should be reviewed.
2.4. Statements/Labeling:
• Storage Statements:
✓ Establish storage statements based on stability evaluations and national/regional
requirements.
✓ Provide specific instructions, especially for products sensitive to freezing.
✓ Avoid vague terms like "ambient conditions" or "room temperature."

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✓ There must be a direct link between the storage statement and the demonstrated stability
of the product.
• Expiration Date:
❖ Display an expiration date on the container label.
3. Appendix:
Provides definitions for key terms used in the guideline, including:
1. Accelerated testing: Using exaggerated conditions to increase degradation rates.
2. Bracketing: Testing only extreme design factors.
3. Climatic zones: World zones based on climatic conditions.
4. Commitment batches: Batches studied post-approval.
5. Container closure system: Packaging components.
6. Dosage form: Pharmaceutical product type.
7. Drug product: Final packaged dosage form.
8. Drug substance: Unformulated active ingredient.
9. Excipient: Inactive ingredients.
10. Expiration date: Date product is expected to remain within specifications.
11. Formal stability studies: Long-term and accelerated studies.
12. Impermeable containers: Barriers to gases and solvents.
13. Intermediate testing: Testing at 30°C/65% RH.
14. Long term testing: Testing at recommended storage conditions.
15. Mass balance: Sum of assay and degradation products.
16. Matrixing: Testing a subset of all possible samples.
17. Mean kinetic temperature: Single temperature representing thermal challenge.
18. New molecular entity: Previously unregistered active substance.
19. Pilot scale batch: Batch simulating production scale.
20. Primary batch: Batch used in formal stability studies.
21. Production batch: Batch made at full production scale.
22. Re-test date: Date for re-examining drug substance.
23. Re-test period: Time drug substance remains within specifications.
24. Semi-permeable containers: Containers allowing solvent passage.
25. Shelf life: Time drug product remains within specifications.
26. Specification: Tests and acceptance criteria.
27. Specification – Release: Suitability at release.
28. Specification - Shelf life: Suitability throughout shelf life.
29. Storage condition tolerances: Acceptable variations in storage conditions.
30. Stress testing (drug substance): Intrinsic stability studies.
31. Stress testing (drug product): Severe condition effect studies.
32. Supporting data: Data supporting analytical procedures and stability.

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