Pharmaceutical Quality Assurance Notes-2025

(VIth Sem)
Prof. (Dr.) Zeenat Iqbal

Unit: 1 ICH GUIDELINES (Quality)

ICH Mission is to achieve greater harmonization to ensure that safe, effective and
high quality medicines should be developed and marketed in the most resource
efficient manner.

Necessity for International Regulatory Guidance

 The increasing globalisation of the pharmaceutical industry is a well-

recognised phenomenon.

 In parallel to the development of medicinal products for use world-wide,

there has been a growing impetus to harmonise the requirements for
registering these products with regulatory authorities in different regions.

 Harmonisation avoids the duplication of work required for registering new

medicinal products, reduce the cost of research and development, over
unnecessary experimentation and the rising cost of healthcare.

 It allows patients faster access to new medicines whilst ensuring that they
are safe, efficacious and of suitable quality—the aim of regulatory
authorities in protecting public health.

 The necessity for international regulatory guidance was recognised in the

1980s, with the successful single market created by the European
Community.

 Europe, Japan and the United States had begun bilateral discussions on the
possibilities of harmonisation but specific plans were not initiated until 1989

Prof. (Dr.) Zeenat Iqbal; Quality Assurance Notes-2025 Page 1

 at a conference organised by the World Health Organisation (WHO) for
Drug Regulatory Authorities.

 A Steering Committee was established at that time.

 The International Conference on Harmonisation of Technical Requirements

for the Registration of Pharmaceuticals for Human Use (ICH) which finally
developed is a tripartite body sponsored by regulators and pharmaceutical
industry from the three major pharmaceutical markets: the United States
(US), European Union (EU) and Japan.

ICH Members (as of November 2020):

 17 Members:

 Founding Regulatory: EC, Europe; MHLW/PMDA, Japan; FDA, United

States

 Founding Industry: EFPIA; JPMA; PhRMA

 Standing Regulatory: Swiss medic, Switzerland; Health Canada, Canada

 Regulatory: ANVISA, Brazil; NMPA, China; HSA, Singapore; MFDS,

Republic of Korea; TFDA, Chinese Taipei; TITCK, Turkey

 Industry: BIO; Global Self-Care Federation; IGBA

 2 Standing Observers: WHO; IFPMA

 32 Observers: Regulatory authorities; Regional Harmonisation Initiatives;

international industry pharmaceutical organisations; international
organisations regulated or affected by ICH Guidelines

The Steering Committee is responsible for identifying and approving topics for
which harmonized guidelines are then developed.

Objectives of ICH:

• To increase international harmonization of technical requirements to ensure

that safe, effective and high quality medicines are developed.
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 • To harmonize technical requirements for registration or marketing approval.

• To develop and register pharmaceuticals in the most effective and cost

efficient manner.

• To promote public health.

• To prevent unnecessary duplication of clinical trials on humans and post

market clinical evaluations

• To minimize the use of animal testing without compromising safety and

effectiveness of drug.

• Development and manufacturing of new medicines.

• Registration and supervision of new medicines.

Mission of ICH:

 Harmonisation for Better Health

 The International Council for Harmonisation of Technical Requirements for

Pharmaceuticals for Human Use (ICH) is unique in bringing together the
regulatory authorities and pharmaceutical industry to discuss scientific and
technical aspects of drug registration.

 ICH's mission is to achieve greater harmonisation worldwide to ensure that

safe, effective, and high quality medicines are developed and registered in
the most resource-efficient manner.

 Harmonisation is achieved through the development of ICH Guidelines via a

process of scientific consensus with regulatory and industry experts working
side-by-side.

 Key to the success of this process is the commitment of the ICH regulators
to implement the final Guidelines.

 To maintain a forum for a constructive dialogue on scientific issues between

regulatory authorities and pharmaceutical industry on harmonization of the
technical products.

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  To contribute to the protection of public health in the interest of patients
from an international perspective.

 To avoid divergent future requirements through harmonization of selected

topics needed as a result of therapeutic advances.

 To facilitate the adoption of new or improved technical research.

 To encourage the adequate implementation and integration of common

standards through the dissemination of the communication of information

Formal ICH Procedure:

The Formal ICH procedure is a step wise procedure consisting 5 steps, which is
further followed for the harmonization of new ICH topics.

Step 1: Consensus building- Technical document

Step 2:

(a) ICH parties consensus on technical document

(b) Draft guideline adoption by regulators

Step 3: Regulatory consultation and discussion

Step 4: Adoption of an ICH harmonized guideline

Step 5: Implementation

The first ICH steering committee meeting (“Terms of Reference”) divided the ICH
topics into four categories: QSEM

“QSEM” stands for Quality, Safety, Efficacy and Multidisciplinary guidelines,

which are the basis for approving and authorizing new medicinal products.

The QSEM guidelines of the International Council for Harmonisation (ICH)

cover key aspects of pharmaceutical development and regulation. The acronym
QSEM represents the four main categories of ICH guidelines:

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1. Quality: Covers pharmaceutical quality, including stability, specifications,
impurities, and analytical methods

2. Safety: Focuses on non-clinical safety studies to assess toxicology,

carcinogenicity, and genotoxicity

3. Efficacy: Relates to clinical studies, including study design, endpoints, and

reporting standards. Examples: ICH E6 (Good Clinical Practice – GCP)

4. Multidisciplinary: Covers cross-cutting topics like medical terminology,

electronic submissions, and biopharmaceutics classification, which do not fit
uniquely into the above categories.

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1. Q1 A – Q1F (STABILITY GUIDELINES):

 Q1-A: - Stability testing of new drug substances and products.

The purpose of stability testing is to provide evidence on how the quality of a drug
substances and drug product varies with time under the influence of variety of
environmental factors.

 Q1-B: - Photo-stability testing of new drug and products.

The purpose of photo-stability testing is to provide evidence on how the quality of

drug is effecting by light.

 Q1-C: - Stability testing of new dosage forms.

Gives guidance for new formulations of already approved medicines and defines
the circumstances under which reduced stability can be accepted.

Q1 D (STABILITY GUIDELINES):

 Q1-D :- Bracketing and Matrixing Designs for stability testing of New

Drug substances and Products.

 This guideline is intended to address recommendations on the application of

bracketing and matrixing to stability studies conducted in accordance with
principles outlined in the ICH Q1A(R). This document provides guidance on
bracketing and matrixing study designs. Specific principles are defined in
this guideline for situations in which bracketing or matrixing can be applied.

 Bracketing is the design of a stability schedule such that only samples on

the extremes of certain design factors (e.g., strength, container size and/or
fill) are tested at all time points as in a full design. The design assumes that
the stability of any intermediate levels is represented by the stability of the
extremes tested.

 Matrixing is the design of a stability schedule such that a selected subset of

the total number of possible samples for all factor combinations would be
tested at a specified time point. The design assumes that the stability of each
subset of samples tested represents the stability of all samples at a given time
point.
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  Q1-E :- Evaluation of Stability Data

This addresses the evaluation of stability data that should be submitted in the
registration application for new molecular entities and associated drug products.
The guidelines also provides suggestions on establishing shelf lives for drug
substances and drug products intended for storage at or below room temperature.

 Q1-F:- Stability data package for registration applications in climatic

zones III and IV

For Climatic Zones III (Hot/Dry) and IV (Hot/Humid) in the ICH Q1F guidelines,
the recommended long-term storage conditions for stability testing are 30°C ± 2°C
and 35% RH ± 5% RH for Zone III and 30°C ± 2°C and 65% RH ± 5% RH for
Zone IV.

ICH STABILITY ZONES:

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2. Q2- ANALYTICAL VALIDATION:

 Validation of analytical procedures.

 The objective of validation of an analytical procedure is to demonstrate that

it is suitable for its intended purpose

 Gives validation parameters needed for a variety of analytical methods.

 Discusses the characteristics that must be considered during the validation of

analytical procedure.

 Types of Analytical Procedures to be Validated :-

- Identification tests;

- Quantitative tests for impurities content;

- Limit tests for the control of impurities;

- Quantitative tests of the active moiety in samples of drug substance

3. Q3-– Q3-D - IMPURITIES:

Organic Impurities:

 Starting materials

 By-products

 Intermediates

 Degradation products

Reagents, ligands and catalysts

Inorganic Impurities:

 Reagents, ligands and catalysts

 Heavy metals or other residual metals

 Inorganic salts

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  Other materials (e.g., filter aids, charcoal)

Residual Solvents:

Solvents are inorganic or organic liquids used as vehicles for the preparation of
solutions or suspensions in the synthesis of a new drug substance.

Q3-B: - Impurities in new drug products.

o This guideline addresses only those impurities in new drug products

classified as degradation products of the drug substance or reaction products
of the drug substance with an excipient and/or immediate container closure
system.

o Impurities arising from excipients, leached or extracted from the container

are not covered.

 Identified Degradation Product: A degradation product for which a

structural characterisation has been achieved.

 Identification Threshold: A limit above (>) which a degradation product

should be identified.

 Qualification Threshold: A limit above (>) which a degradation product

should be qualified.

 Reporting Threshold: A limit above (>) which a degradation product

should be reported.

Q3-C: - Impurities- Guideline for residual solvents.

The objective of this guideline is to suggest acceptable amounts for residual

solvents in pharmaceuticals for the safety of the patient.

The guideline recommends use of less toxic solvents and describes levels
considered to be toxicologically acceptable for some residual solvents.

 Class 1 solvents: Solvents to be avoid

• Known human carcinogens, strongly suspected human carcinogens, and

environmental hazards.

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  Class 2 solvents: Solvents to be limited

• Non-genotoxic animal carcinogens or possible causative agents of other

irreversible toxicity such as neurotoxicity or teratogenicity. Solvents
suspected of other significant but reversible toxicities.

 Class 3 solvents: Solvents with low toxic potential

• Solvents with low toxic potential to man; no health-based exposure limit is

needed. Class 3 solvents have PDEs of 50 mg or more per day

• Q3 D- :- Impurities- Guideline for elemental elements

Elemental impurities in drug products may arise from several sources:

• They can be residual catalysts that were added intentionally in synthesis, or

• may be present as impurities.(e.g., through interactions with processing

equipment or container/closure systems or by being present in components
of the drug product).

Because elemental impurities do not provide any therapeutic benefit to the

patient, their levels in the drug product should be controlled within acceptable
limits.

4. Q4A – Q4B – PHARMACOPOEIAS:

 Q4A :- Pharmacopoeial Harmonisation

The pharmacopoeial authorities, working together through the Pharmacopoeial

Discussion Group (PDG), have been closely involved with the work of ICH since
the outset and harmonisation between the major pharmacopoeias, which started
before ICH, has proceeded in parallel.

 Q4B :- Evaluation and Recommendation of Pharmacopoeial Texts for use in

the ICH regions

This document describes a process for the evaluation and recommendation by the
Q4B Expert Working Group (EWG) of selected pharmacopoeial texts to facilitate

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their recognition by regulatory authorities for use as interchangeable in the ICH
regions.

5. Q5A – Q5E – QUALITY OF BIOTECHNOLOGICAL PRODUCTS:

 Q5A (R1):- Viral Safety Evaluation of Biotechnology Products Derived

from Cell Lines of human or animal origin

• This document is concerned with testing and s evaluation of the viral safety
of biotechnology products derived from characterized cell lines of human or
animal origin and outlines data that should be submitted in the marketing
application/registration package.

 Q5B :- Analysis of the expression construct in cells used for production

of r-DNA derived protein products.

• This document presents guidance regarding the characterisation of the

expression construct for the production of recombinant DNA protein
products in eukaryotic and prokaryotic cells.

6. Q6-A – Q6-B – SPECIFICATIONS:

• Q6 A: - Specifications: Test Procedures and Acceptance Criteria for new

drug substances and new drug products.

The main objective of this guideline is to establish a single set of global

specifications for new drug substances and new drug products.

A specification is defined as a list of tests, references to analytical procedures, and

appropriate acceptance criteria, which are numerical limits, ranges.

This guideline addresses specifications, i.e; those test, procedures and acceptance
criteria which play a major role in assuring the quality of a new drug substances
and new drug product during shelf life.

Q6 B- Specifications:- Test Procedures and Acceptance Criteria for Biological

Products.

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 • This guidance document provides general principles on the setting and
justification, to the extent possible, of a uniform set of international
specifications for biotechnological and biological products to support new
marketing applications.

• The principles explained in this document apply to proteins and

polypeptides, their derivatives, and products of which they are components.

• This document may also apply to other product types such as proteins and
polypeptides isolated from tissues and body fluids. To determine
applicability, manufacturers should consult with the appropriate regulatory
authorities.

• It does not cover antibiotics, synthetic peptides and polypeptides, heparins,

vitamins, cell metabolites, DNA products, allergenic extracts, conventional
vaccines, cells, whole blood, and cellular blood components.

• A valid biological assay to measure the biological activity should be

provided by the manufacturer.

7. Q7 – GOOD MANUFACTURING PRACTICE:

 This document is intended to provide guidance regarding good

manufacturing practice (GMP) for the manufacturing of active
pharmaceutical ingredients (APIs) under an appropriate system for
managing quality.

 Its primary goal is to ensure that APIs meet the requisite quality and purity
standards suitable for their intended use in medicinal products.

Why cGMP is important??

A consumer usually can’t detect that a product is safe or it will work.

Therefore, it is necessary to built quality into the products and manufacture them
under the compliance of cGMP.

cGMP is needed :

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 • To minimize contamination for ex. : Microbial contamination

• To eliminate errors, mixups, deviations and failures.

• To produce product of consistent quality

• Ensures rejects, recalls of drug product.

• Customer satisfaction and protection

• Fulfilling legal requirements

• Pharmaceutical company image and reputation

• Good business practice and pride in workplace

8. Q8 – PHARMACEUTICAL DEVELOPMENT:

• This guideline is mean to provide guidance on the contents of

Pharmaceutical Development of drug products.

• The aim of pharmaceutical development is to design a quality product and

its manufacturing process to consistently deliver the intended performance
of the product.

• This guideline is intended to provide guidance on the contents of Section

3.2.P.2 (Pharmaceutical Development) for drug products as defined in the
scope of Module 3 of the Common Technical Document.

• This section also describes the type of dosage form and formulation that are
suitable for intended use.

9. Q9 – QUALITY RISK MANAGEMENT:

• The purpose of this document is to offer a systematic approach to quality

risk management.

• This guideline provides principles and tools for quality risk management that
can be applies to all aspects of pharmaceutical quality including
development, manufacturing, distribution; and the inspection and

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 submission/review processes throughout the lifecycle of drug substances and
drug products, biological and biotechnological products, including the use of
raw materials, solvents, excipients, packaging and labeling materials.

10. Q10- PHARMACEUTICAL QUALITY SYSTEM:

• This document establishes a new ICH tripartite guideline describing a model

for an effective quality management system for the pharmaceutical industry,
referred to as the Pharmaceutical Quality System.

• ICH Q10 describes one comprehensive model for an effective

pharmaceutical quality system that is based on International Standards
Organisation (ISO) quality concepts, includes applicable Good
Manufacturing Practice (GMP) regulations and complements ICH Q8
“Pharmaceutical Development” and ICH Q9 “Quality Risk Management”.

• This guideline applies to the systems supporting the development and

manufacture of pharmaceutical drug substances (i.e., API) and drug

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 products, including biotechnology and biological products, throughout the
product lifecycle.

11. Q11- DEVELOPMENT & MANUFACTURE OF DRUG SUBSTANCES:

• This guideline describes approaches to developing and understanding the

manufacturing process of the drug substance, and also provides guidance on
what information should be provided in Module 3 of the Common Technical
Document (CTD) Sections 3.2.S.2.2 – 3.2.S.2.6 (ICH M4Q).

• It addresses aspects of development and manufacture that pertain to drug

substance, including the presence of steps designed to reduce impurities.

• ICH Q11 provides further clarification on the principles and concepts

described in ICH Guidelines on Pharmaceutical Development (Q8), Quality
Risk Management (Q9) and Pharmaceutical Quality System (Q10) as they
pertain to the development and manufacture of drug substance.

12. Q12- LIFECYCLE MANAGEMENT:

• This guideline provides a framework to facilitate the management of post-

approval CMC changes in a more predictable and efficient manner.

• A harmonized approach regarding technical and regulatory considerations

for lifecycle management will benefit patients, industry, and regulatory
authorities by promoting innovation and continual improvement in the
pharmaceutical sector, strengthening quality assurance and improving
supply of medicinal products.

13. Q13- CONTINOUS MANUFACTURING OF DRUG SUBSTANCES &

DRUG PRODUCTS:

• ICH Q13 provides a comprehensive framework for the development,

implementation, operation, and lifecycle management of continuous
manufacturing (CM) processes for both drug substances and drug products.
This guideline applies to chemical entities and therapeutic proteins, covering
new products and the transition from batch to continuous manufacturing for
existing products.

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 • The adoption of CM, as outlined in ICH Q13, aims to improve
manufacturing efficiency, agility, and flexibility, potentially leading to
enhanced product quality and reduced production costs.

Key aspects of ICH Q13 include:

 Scientific and Regulatory Considerations: Guidance on the development

and regulatory expectations for CM processes.

 Process Dynamics and Control: Emphasis on understanding process

dynamics, implementing robust control strategies, and ensuring material
traceability.

 Quality Assurance: Ensuring product quality and consistency through

effective process monitoring and control.

14. Q14- ANALYTICAL PROCEDURE DEVELOPMENT:

• ICH Q14 offers guidance on science and risk-based approaches for

developing and maintaining analytical procedures essential for assessing the
quality of drug substances and products.

• This guideline complements ICH Q2(R2) on analytical procedure validation

and applies to new or revised analytical procedures used for release and
stability testing of commercial drug substances and products, both chemical
and biological/biotechnological.

“Quality” is built into a “Product”, and not just tested into a finished product.

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