Quality Control and Quality

Assurance-MQA103T
Dr. Ketan Shah, Professor & Principal
Quality Assurance, SNLPCP

1
 CHAPTER-1.1
Introduction to QA, QC and GMP

2
 Introduction

Quality:
Quality of medicinal product is measured by it’s fitness for purpose.

Safety and efficacy are also a part of quality.

3
 Introduction

4
https://www.slideshare.net/ceutics1315/quality-assuranceandregulatorycomplianceforpharmaceuticalproduct4
 Introduction

Quality assurance:
It is the sum total of organized arrangements with the objective of ensuring
that products will be of the quality required for their intended use.

GMP:
It is the part of quality assurance aimed at ensuring that products are
consistently manufactured to a quality appropriate to their intended use.

5
 Introduction

Quality Control:

• It is the part of GMP concerned with sampling, specification and testing,

documentation and release procedures which ensure that the necessary and
relevant tests are performed and the product is released for use only after
ascertaining it’s quality.

6
 Introduction

Quality Assurance (QA) Quality Control (QC)

•It is a procedure that focuses on providing •It is a procedure that focuses on fulfilling the
assurance that quality requested will be quality requested.
achieved
•QA is the sum total of organised •QC is that part of GMP which is concerned
arrangements made with the object of with sampling, specifications, testing and
ensuring that product will be of the quality with in the organization, documentation and
required by their intended use. release procedures which ensure that the
necessary and relevant tests are carried out.
7
 Introduction
Quality Assurance (QA) Quality Control (QC)
•All those planned or systemic actions •Operational laboratory techniques and
necessary to provide adequate confidence activities used to fulfill requirement of quality
that a product will satisfy the requirements
for quality
•QA aims to prevent the defect •QC aims to identify and fix defects

•QA is company based •QC is lab based

•QA is process oriented •QC is product based

8
 Introduction
GMP- A set of principles and procedures which when followed by manufacturers
for therapeutic goods, helps ensure that the products manufactured will have
the required quality.

GMP covers all aspects of production, from the starting materials, premises and
equipment to the training and personal hygiene of staff.

The quality of a formulation or a bulk drug depends on the quality of those

producing it.

GMP is the magic key that opens the door of quality.

9
 GMP
Good Manufacturing Practices Worldwide Enforcement

Good Manufacturing Practices are enforced in the United States by the FDA
In the United Kingdom by the Medicines and Healthcare Products Regulatory
Agency
GMPs are enforced in Australia by the Therapeutic Goods Administration
In India by the Ministry of Health, Govt. of India
Many underdeveloped countries lack GMPs

10
 GMP
“cGMP” – where c = current, to emphasize that the expectations are dynamic

It reminding manufacturers that they must employ technologies and systems

which are up- to date in order to comply with the regulation.

GMP = Good Manufacturing Practice Without validation terminology its a GMP.

cGMP = Good Manufacturing Practice With validation terminology its a cGMP.

11
 GMP
GMP in solid dosage forms
GMP in semisolid dosage forms
GMP in liquid orals
GMP in parenterals production
GMP in Ayurvedic medicines
GMP in Biotechnological products
GMP in Nutraceuticals and cosmeceuticals
GMP in Homeopathic medicines

12
 Principles of GMP
1. Design and construct the facilities and equipments properly
2. Follow written procedures and instructions
3. Document work, Validate work
4. Monitor facilities and equipment
5. Write step by step operating procedures and work on instructions
6. Design, develop and demonstrate job competence
7. Protect against contamination
8. Control components and product related processes
9. Conduct planned and periodic audits
13
 Important Documents in GMP
• Policies
• SOP
• Specifications
• MFR
• BMR
• Manuals
• Master Plans/files
• Validation Protocols
• Forms and Formats
• Records

14
CHAPTER-1.2
GLP

15
 Introduction

Definition: Quality system concerned with the organisational process

and the conditions under which non-clinical health and environmental
safety studies are planned, performed, monitored, recorded, archived
and reported.

It applies to nonclinical studies

It helps assure regulatory authorities that the data submitted are a true.

16
 Introduction
Scope of GLP:
Principles of GLP apply to all non-clinical health and environment safety studies
required by regulations for the purpose of registering or licensing.
• Pharmaceuticals
• Pesticides
• Food additives
• Feed additives
• Cosmetic products
• Veterinary drug products and similar products
• Industrial chemicals 17
 PRINCIPLES OF GLP
• Promote the development of quality tool data
• Considered as a set of standards for ensuring the quality
• Requires to assign roles and responsibility to staff

18
 Introduction
Quality Assurance Unit:

1) An individual or group designated by management to assure that the studies

are compliance with GLP principles.
2) Monitors study to assure management that the facilities like; equipment,
Personnel, Method, Practices, Record, Controls are conformance with the
regulation.
3) Maintain the copies of master schedule sheet, protocol and SOPs.
4) Access to updates study plans and SOPs.

19
 Introduction
Quality assurance unit:

5) Documented verification of compliance of study with GLP principles.

6) Inspections to determine the compliance of the study with GLP principles and
three type of inspection are:
1) Study based inspection
2) Process based inspection
3) Facility based inspection
7) Determines any deviation from the approved protocol and containing dates
and type of inspection.
20
 Introduction
Organization and Personnel
• Organizational chart should be prepared and should be kept up to
date.
• Number of personnel available should be sufficient to perform the
tasks in a timely manner.
• Responsibility should be defined
• Role of study director

21
 Introduction
Protocol for conduct of non clinical testing:
CONTENTS OF PROTOCOL
1) Identification
2) Title and statement of purpose
3) Identification of test (or control) items
4) Name and address of the sponsor, test facility and
test site
5) Name of study director and other personnel
6) Proposed dates
7) Justification of selection of test sample
8) Description of test sample
9) Experimental design
22
 CONTROL ON ANIMAL HOUSE
LOCATION OF THE ANIMAL HOUSE
• It should be separate building.
• It should be Clean and hygienic.
• It should be protected from insects.
• Animal house should have maximum number of room.
• It should have quarantine area, so that new animals can be held for
observation.
• It should have extra space for office, surgery, stores, washings, sterilizing,

23
 CONTROL ON ANIMAL HOUSE
MAINTENANCE OF ANIMAL HOUSE:
• Animals should live in comfort and psychologically acceptable habitate.
• Over crowding should not be permitted.
• Small animals like rat, mice should be kept in cages which are built of plastic,
galvanized iron or aluminium etc.
DIET:
• Must be sufficient in quantity to cover energy required.
• It should be correct quality to satisfy biological need.
• It should be appetizing.
24
 CONTROL ON ANIMAL HOUSE
CLEANLINESS:
• Animals will not live under dirty condition.
• They should be kept clean, otherwise there is a risk of epidermal disease.
• Weekly once, animals should be transferred to clean cages.
LITTERS:
• A layer of absorbent material should be spread to a depth of ½ - 1 inch on the
bottom of cage.
• Fine soft wood, wood shavings, sugar cane pith can be used for absorbent.
• Pregnant animals must be supplied with nesting materials.
25
 CONTROL ON ANIMAL HOUSE
CAGES:
Each species of animals requires its own type of cage.
• It should have enough room for free movement and space for resting.
• Cage should have holder for SMALL CARD.
• The card should contain
THE NAME OF EXPERIMENT, IDENTIFYING MARK OF THE ANIMALS, DATA AND
RELEVANT MATTER IS WRITTEN

• Card must not be remove before conclusion of experiment

26
 CONTROL ON ANIMAL HOUSE
VENTILATION
• Ideally all the animal house should be air conditioned, if not adequate
ventilation from windows should be ensured
• The exhaust air should be discharged in a manner where it cannot re enter
buildings

27
 CONTROL ON ANIMAL HOUSE
TEMPERATURE AND HUMIDITY
• The animal house temp. Must be maintained
• Sudden fluctuation in temperature must be avoided
• The humidity of the animal house must be moderate depending on the animal
habitat;
Rabbit - 45 %
Mice - 65 %
PREVENTION OF DISEASE:
• The new animal should be kept in a special quarantine room and kept for
observation 10 – 14 days, animal sick should be held in quarantine 28
 Report preparation and documentation
GLP requires documentation and verification of actions and variables that could
impact the outcome of a study.
A good GLP report is readable.
The relationship with the contract laboratory is essential to success.

29
 Documentation
• Name and address of test facility
• Dates of start and finish, Name of study director
• Objectives
• Details of test/control substance and vehicles
• Description of test system
• Details of dosing , route and duration
• Statistics, Discussion, References
• GLP compliance statement from study director
• QA statement of inspections/Audits
• Signed /dated reports from scientists
30
 CPCSEA
CPCSEA: Committee for the Purpose of Control And Supervision of Experiments on
Animals.
Good Laboratory Practices (GLP) for animal facilities is intended to assure quality
maintenance and safety of animals used in laboratory studies while conducting
biomedical and behavioural research and testing of products.

GOAL:
• To promote the humane care of animals.
• Testing with the basic objective of providing specifications that will enhance
animal well-being.
• Improve quality in the pursuit of advancement of biological knowledge of
humans and animals. 31
 CPCSEA
Functions of CPCSEA:
•Registration of establishments conducting animal experimentation or breeding
of animals for this purpose.
•Selection and appointment of nominees in the Institutional Animal Ethics
Committees of registered establishments.
•Approval of Animal House Facilities on the basis of reports of inspections
conducted by CPCSEA.
•Permission for conducting experiments involving use of animals.
•Recommendation for import of animals for use in experiments.
•Action against establishments in case of violation of any legal norm/stipulation.
32
 CPCSEA
VETERINARY CARE:

• Adequate veterinary care provided by qualified person.

• Daily observation of animals can be done by someone else.
• There must be a mechanism for direct communication with the veterinarian.
• Veterinarian must contribute in formation of policies and procedures for –
Veterinary care.
– Animal care.
– Animal husbandry.
– Monitoring occupational health hazards.
– Zoonosis control programme.

33
 CPCSEA
ANIMAL PROCUREMENT:

• Animal must be acquired legally as per CPCSEA guidelines.

• Health surveillance programme for screening of incoming animals.

• Methods of transportation must be taken into account

• Each consignment of animal should be inspected for compliance with

procurement specification.

• The animal should be quarantined and stabilised.

34
 CPCSEA
QUARANTINE
• Separation of newly received animals from those already in the facility until the
health and possibly the microbial status of newly received animal have been
determine
• A minimum duration of quarantine for small animal -1 week and for larger
animal - 6 week.

STABILIZATION:
• Physiologic, psychological and nutritional stabilization should be given before
their use.
• Duration of stabilization will depend on type and duration of animal
transportation , and species of animal.
35
 CPCSEA
SEPARATION:

• Physical separation of animal by species is recommended to prevent

interspecies disease transmission and to eliminate anxiety and possible
physiological and behavioural changes due to interspecies conflict.

• Housing different species in separate room.

• It shall be acceptable to house different species in the same room ,e.g. two
species have a similar pathogen status and are behaviourally compatible.

36
 CPCSEA
SURVEILLANCE, DIANGOSIS, TREATMENT AND CONTROL OF DISEASE:

• Daily observation for signs of illness, injury and abnormal behaviour.

• Unexpected deaths and signs of illness and distress are to be reported promptly
to ensure proper care

• Animal is isolated during the entire process of treatment.

37
 CPCSEA
ANIMAL CARE AND TECHNICAL PERSONNEL:
Animal care programs require technical and husbandry support.
Institutions should employ people trained in laboratory animal science.
Formal and on the job training should be given.

PERSONAL HYGIENE:
Animal care staff should maintain a high standard of personal cleanliness.
Clothing suitable for use in the animal facility should be supplied and laundered by
the institution.
Institutional facilities should be used to decontaminate clothing.
Use disposable gear such as gloves, masks, head covers, coats, coveralls and shoe
covers.
Outer garments worn in the animal rooms should not be worn outside. 38
 CPCSEA
CPCSEA GUIDELINES ANIMAL EXPERIMENTATION INVOLVING HAZARDOUS AGENTS:

• Governing policies should be made by institution.

• Institutional Bio safety Committee are in place in higher level institutions.
• Institutional Biosafety Committee (IBSC) members:

– Head of the institution or his nominee.

– 3 or more scientists engaged in DNA work or molecular biology with an outside
expert in the relevant discipline.
– A member with medical qualification-Bi-safety officer (in case of work with
pathogenic agents/large scale used.)
– One member nominated by Department of Bio-Technology (DBT)
39
 CPCSEA
CPCSEA GUIDELINES FUNCTIONS OF IBSC:

• Registration of Bio-safety Committee membership composition with the Review

Committee on Genetic Manipulations (RCGM) and submission of report.
• Review and clearance of project proposals falling under restricted category that
meets the requirements under the guidelines.
• Tailoring bio-safety program to the level of risk assessment.
• Training of personnel on bio safety.
• Instituting health monitoring program for laboratory personnel.
• Adopting emergency plans.

40
 CPCSEA
MULTIPLE SURGICAL PROCEDURES ON SINGLE ANIMAL:

• Multiple surgical procedures on a single animal for any testing or experiment

are not to be practiced unless specified in a protocol only approved by the IAEC.

CPCSEA GUIDELINES DURATIONS OF EXPERIMENTS:

• No animal should be used for experimentation for more than 3 years unless
adequate justification is provided.

41
 CPCSEA
PHYSICAL FACILITIES :

• BUILDING MATERIALS - moisture-proof, fire-resistant, seamless materials are

most desirable for interior surfaces including vermin and pest resistance.

• CORRIDOR - wide enough to facilitate the movement of personnel as well as

equipments and should be kept clean.

• UTILITIES - water lines, drain pipes and electrical connection

• ANIMAL ROOM DOORS - rust, vermin and dust proof. it properly within their
frames and provided with an observation window.

• FLOORS - smooth, moisture proof, non-absorbent, skid-proof. 42

 CPCSEA
DRAINS
Floor drains are not essential in all rooms used exclusively for housing rodents.

WALLS & CEILINGS- free of cracks, unsealed utility penetrations, or imperfect

junction with doors, ceilings, floors and corners.

STORAGE AREAS- separate storage areas should be designed for feed, bedding,
cages and materials not in use.

FACILITIES FOR SANITIZING EQUIPMET AND SUPPLIES- an area for sanitizing

cages and ancillary equipment is essential with adequate water supply.

EXPERIMENTAL AREA- should be carried out in a separate area from the place
where animals are housed. 43
 CPCSEA
ENVIRONMENT :
Air conditioning is for laboratory animals. temperature with in the range of 180 -
290c relative humidity- 30-70% throughout the year

For large animal comfortable zone -18 -370c

POWER & LIGHTING

The electrical system should be safe and provide appropriate lighting and a
sufficient no. of power outlets.
A time control light system should be used.

NOISE CONTROL- noise free environment

44
 CPCSEA
ANIMAL HUSBANDRY:

CAGING & HOUSING SYSTEM-

Feeding and watering devices should be easily accessible for filing, changing,
cleaning and servicing.

Cages made of steel or painted steel

Keep the animal dry and clean

Meet the biological need of animal

Adequate ventilation 45
 CPCSEA
FOOD

• Animals should be fed palatable, non-contaminated, and nutritionally adequate

food daily unless the experimental protocol requires otherwise.
• Feeders should allow easy access to food, while avoiding contamination by
urine and faeces.
• Laboratory animal diets should not be manufactured or stored in facilities used
for farm feeds
• Areas in which diets are processed or stored should be kept clean and enclosed
to prevent entry of insects or other animals.
• Precautions should be taken if perishable items such as meats, fruits, and
vegetables are fed.
46
 CPCSEA
BEDDING:

Bedding should be absorbent, free of toxic chemicals or other substances that

could injure animals or personnel, and of a type not readily eaten by animals.
Bedding should be removed and replaced with fresh materials as often as
necessary to keep the animals clean and dry. It is ideal to change the bedding
twice a week.
Nesting materials for newly delivered animals wherever can be provided (e.g.
Paper, tissue paper, cotton etc.).

47
 CPCSEA

WATER:
Ordinarily animals should have continuous access to fresh, potable,
uncontaminated drinking water, according to their particular requirements.

Periodic monitoring of microbial contamination in water is necessary.

Watering devices, such as drinking tubes and automatic waterers if used should
be examined routinely.

It is better to replace water bottles than to refill them.

48
 CPCSEA
SANITATION:

Animal rooms, corridors, storage spaces, and other areas should be cleaned with
appropriate detergents and disinfectants.

Cleaning utensils, such as mops, pails, and brooms, should not be transported
between animal rooms.

Where animal waste is removed by hosting or flushing, this should be done at least
twice a day. Animals should be kept dry during such procedures.

Cages should be sanitised before animals are placed in them.

49
 CPCSEA
SANITATION CLEANLIESS

Sanitation is essential in an animal facility. Animal rooms, corridors, storage spaces,

and other areas should be cleaned with appropriate detergents and disinfectant.

50
 CPCSEA
Waste disposal

• Wastes should be removed regularly and frequently. All waste should be

collected and disposed in a safe and sanitary manner. The most preferred
method of waste disposal is incineration.

EMERGENCY, WEEKEND AND HOLIDAY CARE

• Animal should be cared for by qualified personnel every day, including

weekends and holidays, to safeguards their well- being including emergency
veterinary care
51
 CPCSEA
RECORD KEEPING
The Animal House should maintain following records:
• Animal House plans, which includes typical floor plan, all fixtures etc.
• Animal House staff record - both technical and non - technical
• Health record of staff! animals.
• All SOPs relevant to the animals
• Breeding, stock, purchase and sales records
• Minutes of institute Animals Ethics Committee Meetings
• Records of experiments conducted with the number of animals used (copy of Form b)
• Death Record and Clinical record of sick animals
• Training record of staff involved 52
 CPCSEA
STANDARD OPERATING PROCEDURES (SOPs)

Guidelines should contain:

• Name of the Author
• Title of the SOP
• Date of preparation
• Reference of previous SOP on the same subject and date (Issue no and Date)
• Location and distribution of SOPs with sign of each recipient

53
 CPCSEA
Objectives

• Detailed information of the instruments used

• The name of the manufacturer of the reagents and the methodology of the
analysis pertaining to animals.

• Normal value of all parameters

• Hazard identification and risk assessment

54
 CPCSEA
ANAESTHESIA AND EUTHANASIA:

• The scientists should ensure that the painful procedure are conducted under
appropriate anaesthesia.
• Anaesthesia is given for the full duration of experiment and at no stage the
animal is conscious to perceive pain during the experiment.
• If at any stage during the experiment the investigator feels that he has to
abandon the experiment or he has inflicted irreparable injury, the animal
should be sacrificed.
• In the event of a decision to sacrifice an animal on termination of an
experiment or other wise an approved method of euthanasia should be
adopted.
55
 CPCSEA
LABORATORY ANIMAL ETHICS:

• From the ethical point of view it is important that such considerations are
taken care at the – Individual level – Institutional level – National level.

56
 CHAPTER-1.3
OVERVIEW OF ICH GUIDELINE

57
 Introduction

Since its inception in 1990, ICH has gradually evolved, to respond to the
increasingly global face of drug development.

Mission: To achieve greater harmonisation worldwide to ensure that safe,

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

On 23 October 2015, ICH announced organisational changes as its marks 25

years of successful harmonisation.

58
 Introduction
2. TYPE OF ICH GUIDELINES
2.1 Q Guideline (Quality guideline)
2.2 S Guideline (Safety Guideline)
2.3 E Guideline (Efficacy Guideline)
2.4 M Guideline (Multidisciplinary Guideline)

59
 Q Guideline

2.1 Harmonisation achievements in the Quality area include 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 managements.
2.1.1 TYPE OF Q GUIDELINE
Q1A – Q1F Stability
Q2 Analytical Validation
Q3A – Q3D Impurities
60
 Q Guideline
Q4 – Q4B Pharmacopoeias
Q5A – Q5E Quality of Biological 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

61
 Q Guideline
Q12 Lifecycle Management
Q13 Continuous Manufacturing of Drug Substances and Drug Products
Q14 Analytical Procedure Development

62
 Q Guideline
1. Q1A – Q1F Stability
Q1A (R2) Stability Testing of New Drug Substances and Products:
Provides recommendations on stability testing protocols including temperature,
humidity and trial duration for climatic Zone I and II.
Q1B Stability Testing: Photostability Testing of New Drug Substances and Products:
This forms an annex to the main stability Guideline, and gives guidance on the basic
testing protocol required to evaluate the light sensitivity and stability of new drugs
and products.
Q1C Stability Testing for New Dosage Forms:
Guideline for new formulations of already approved medicines and defines the
circumstances under which reduced stability data can be accepted.

63
 Q Guideline
Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances
and Products:
Describes general principles for reduced stability testing and provides examples of
bracketing and Matrixing designs.
Q1E Evaluation of Stability Data:
Explains situations where extrapolation of retest periods/shelf-lives beyond the real-
time data may be appropriate.
Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV:
The ICH steering Committee endorsed the withdrawal of the Q1F Guideline at its
meeting in Yokohama, June 2006 and decided to leave definition of storage
conditions in Climatic Zones III and IV to the respective regions and WHO.

64
 Q Guideline
Q2 Analytical Validation
Q2 (R2)/Q14 Analytical Procedure Development and Revision of Q2 (R1)
Analytical Validation:
The Q2 (R2)/Q14 EWG will develop a new ICH Quality Guideline, ICH Q14, on
Analytical Procedure Development, and revise the ICH Q2 (R1) Guideline on
Validation of Analytical Procedures, with a view to potentially combine both
documents into one, for simplification and clarity.

Q2 (R1) Revision
The scope of the revision of ICH Q2(R1) will include validation principles that
cover analytical use of spectroscopic or spectrometry data some of which often
require multivariate statistical analyses.
65
 Q Guideline
Q14 Analytical Procedure Development Guideline
The new guideline is proposed to harmonise the scientific approaches of
Analytical Procedure Development, and to provide the principles relating to the
description of Analytical Procedure Development Process.

Q2 (R1) Validation of Analytical Procedures: Text and Methodology:

This identifies the validation parameters needed for a variety of analytical
methods.
It also discusses the characteristics that must be considered during the validation
of the analytical procedures which are included as part of registration
applications.

66
 Q Guideline
Q3A – Q3D Impurities
Q3A (R2) Impurities in New Drug Substance:
The Guideline addresses the chemistry and safety aspect of impurities, including
the listing of impurities in specifications and defines the thresholds for reporting,
identification and qualification.

Q3B (R2) Impurities in New Drug Products:

It complements the Guideline on impurities in new drug substances and provides
advice in regard to impurities in products containing new, chemically synthesized
drug substances.
The Guideline specifically deals with those impurities which might arise as
degradation products of the drug substance or arising from interactions between
drug substance and excipients or components of primary packaging materials.
67
 Q Guideline
Q3A – Q3D Impurities
Q3C (R7) Impurities: Guideline for Residual solvents:
This recommends the use of less toxic solvents in the manufacture of drug
substances and dosage forms, and sets pharmaceutical limits for residual solvents
in drug products.

68
 Q Guideline
Q3C (R8) Impurities: Guideline for Residual solvents:
The Q3C(R8) EWG is currently undertaking a maintenance of the Guideline, which
will result in the future Q3C(R8) version, to develop PDE levels for three solvents:
2-methyltetrahydrofuran, cyclopentylmethylether and tert-butanol.

Q3D (R1) Guideline for Elemental impurities:

ICH Q3D Elemental Impurities is a quality guideline for the control of elemental
impurities in new drug products, and it establishes Permitted Daily Exposures for
24 Elemental Impurities for drug products administered by the oral, parenteral and
inhalation routes of administration.

69
 Q Guideline
Q3D (R2) Revision of Q3D (R1) for cutaneous and transdermal products:
ICH Q3D(R1) Elemental Impurities is a quality guideline for the control of elemental
impurities in new drug products, and it establishes Permitted Daily Exposures for
24 Elemental Impurities for drug products administered by the oral, parenteral and
inhalation routes of administration.

Q3D Training Implementation of Guideline for Elemental impurities:

Throughout the development of the Q3D Guideline, external audiences,
constituents and interested parties have clearly communicated the complexity of
the implementation approaches for this guideline.
While the Q11 Guideline provides the framework, it cannot provide the detailed
examples covering the breadth of potential case studies for products within scope
of the guideline.
70
 Q Guideline
1. Q4 – Q4B Pharmacopoeias
i. Q4 Pharmacopoeias:
Q6A activity provided the framework on how to set specifications for drug
substances.
The resulting ICH Q6A Guideline provides harmonised guidance in this area.
With the passage of the Chemical Substances (Q6A) ICH Guideline, the
harmonisation of several compendial test chapters has been considered as critical
by the ICH Steering Committee.
The three organisations conduct their harmonisation efforts through a tripartite
pharmacopoeial harmonisation program known as the Pharmacopoeial
Discussion Group.
71
 Q Guideline
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 of selected pharmacopoeial texts to facilitate their
recognition by regulatory authorities for use as interchangeable in the ICH regions
and since 2010 in Canada.
72
 Q Guideline
Q5A – Q5E Quality of Biotechnological Products
Q5A (R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell
Lines of Human or Animal Origin:
Testing and evaluation of the viral safety of biotechnology products derived from
characterised cell lines of human or animal origin.
Provide a general framework for virus testing experiments for the evaluation of
virus clearance and the design of viral tests and clearance evaluation studies.

Q5B Analysis of the Expression Construct Cells used for Production of r-DNA
Derived Protein Products:
It advises on the types of information that are considered valuable in assessing
the structure of the expression construct used to produce recombinant DNA
derived proteins.
73
 Q Guideline
Q5C Stability Testing of Biotechnological/Biological Products:
This document augments the stability Guideline (Q1A above) and deals with the
particular aspects of stability test procedures needed to take account of the
special characteristics of products in which the active components are typically
proteins and/or polypeptides.

74
 Q Guideline
Q5D Derivation and Characterisation of Cell Substrates used for Production of
Biotechnological/Biological Products:
Provides broad guidance on appropriate standards for the derivation of human
and animal cell lines and microbes used to prepare biotechnological/biological
products and for the preparation and characterisation of cell banks to be used for
production.

Q5E Comparability of Biotechnological/Biological Products Subject to Changes in

their Manufacturing Process:
Provide principles for assessing the comparability of biotechnological/biological
products before and after changes are made in the manufacturing process for the
drug substance or drug product.
75
 Q Guideline
Q6A – Q6B Specification
Q6A Specification: Test Procedure and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances:
This addresses the process of selecting tests and methods and setting
specifications for the testing of drug substances and dosage forms.

Q6B Specifications: Test Procedure and Acceptance Criteria for

Biotechnological/Biological Products:
Provides guidance on justifying and setting specifications for proteins and
polypeptides which are derived from recombinant or non-recombinant cell
cultures.

76
 Q Guideline
Q7 Good Manufacturing Practice
Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients:
Early in the ICH Process it was agreed that there was adequate international
agreement on the technical aspects of Good Manufacturing Practices (GMP) for
Pharmaceutical Products and that further harmonisation action through ICH was
not needed.
Recently, however, attention has focused on the need to formalise GMP
requirements for the components of pharmaceutical products - both active and
inactive.

77
 Q Guideline
Q7 Q&As Questions and Answers: Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients:
Technical issues with regard to GMP of APIs – also in context with new ICH
Guidelines - are addressed in this Question and Answer document in order to
harmonise expectations during inspections, to remove ambiguities and
uncertainties and also to harmonise the inspections of both small molecules and
biotech APIs.

78
 Q Guideline
Q8 Pharmaceutical Development
Q8 (R2) Pharmaceutical Development:
Provide guidance on the contents of Pharmaceutical Development for drug
products as defined in the scope of Module 3 of the Common Technical
Document.
The guideline does not apply to contents of submissions for drug products during
the clinical research stages of drug development.

79
 Q Guideline
Q8/Q9/Q10 Implementation:
Since reaching Step 4 and publication within the ICH regions, experiences by all
parties with the implementation of the ICH Q8(R2), Q9 and Q10 Guidelines have
resulted in the need for some clarification.
The Questions and Answers developed by the Quality Implementation Working
Group are intended to facilitate the implementation of the Q8(R2), Q9 and Q10
Guidelines, by clarifying key issues.

80
 Q Guideline
SURVEILLANCE, DIANGOSIS, TREATMENT AND CONTROL OF Q9 Quality Risk
Management

Q9 Quality Risk Management:

This Guideline provides principles and examples of tools of quality risk
management that can be applied to all aspects of pharmaceutical quality
including development, manufacturing, distribution, and the inspection and
submission/review processes throughout the lifecycle of drug substances and
drug (medicinal) products, biological and biotechnological products, including the
use of raw materials, solvents, excipients, packaging and labeling materials.

81
 Q Guideline
Q10 Pharmaceutical Quality System:
This Guideline applies to pharmaceutical drug substances and drug products,
including biotechnology and biological products, throughout the product lifecycle.
The elements of Q10 should be applied in a manner that is appropriate and
proportionate to each of the product lifecycle stages, recognizing the differences
among, and the different goals of each stage.

82
 Q Guideline
Q11 Development and Manufacture of Drug Substances
Q11 Development and Manufacture of Drug Substances (Chemical Entities and
Biotechnological/Biological Entities):
This new guidance is proposed for Active Pharmaceutical Ingredients harmonising
the scientific and technical principles relating to the description and justification
of the development and manufacturing process of Drug Substances including
both chemical entities and biotechnological/biological entities.

Q12 Lifecycle Management

Q12 Technical and Regulatory Considerations for Pharmaceutical Product
Lifecycle Management:
This new guideline is proposed to provide guidance on a framework to facilitate
the management of post-approval Chemistry, Manufacturing and Controls (CMC)
changes in a more predictable and efficient manner across the product lifecycle.
83
 Q Guideline
Q13 Continuous Manufacturing of Drug Substances and Drug Products:
This new Guideline is proposed to:
• Capture key technical and regulatory considerations that promote
harmonisation, including certain Current Good Manufacturing Practices (CGMP)
elements specific to Continuous Manufacturing (CM).
• Allow drug manufacturers to employ flexible approaches to develop,
implement, or integrate CM for the manufacture – drug substances and drug
products – of small molecules and therapeutic proteins for new and existing
products.
• Provide guidance to industry and regulatory agencies regarding regulatory
expectations on the development, implementation, and assessment of CM
technologies used in the manufacture of drug substances and drug products.
84
 Q Guideline
Q14 Analytical Procedure Development
Work on the development of the Q14 Guideline on Analytical Procedure
Development is performed by the Q2 (R2)/Q14 EWG.

85
 S Guideline
2.2 ICH has produced a comprehensiveAset of safety Guidelines to uncover
potential risks like carcinogenicity, genotoxicity and reprotoxicity.

86
 S Guideline
2.2.1 TYPE OF S GUIDELINE A
1. S1A – S1C Carcinogenicity Studies
2. S2 Genotoxicity Studies
3. S3A – S3B Toxicokinetics and Pharmacokinetics
4. S4 Toxicity Testing
5. S5 Reproductive Toxicity
6. S6 Biotechnological Products
7. S7A –S7B Pharmacology Studies
8. S8 Immunotoxicology Studies
9. S9 Nonclinical Evaluation for Anticancer Pharmaceuticals
10. S10 Photosafety Evaluation
11. S11 Nonclinical Paediatric Safety

87
 S Guideline

1. S1A – S1C Carcinogenicity Studies

S1 (R1) Rodent Carcinogenicity Studies for Human Pharmaceuticals:

S1A Need for Carcinogenicity Studies of Pharmaceuticals:

S1B Testing for Carcinogenicity of Pharmaceuticals:

S1C(R2) Dose Selection for Carcinogenicity of Pharmaceuticals:

88
 S Guideline

2. S2 Genotoxicity Studies
S2 (R1) Guidance on Genotoxicity Testing and Data Interpretation for
Pharmaceuticals Intended for Human Use:
S2A: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for
Pharmaceuticals;
S2B: Genotoxicity: A Standard Battery for Genotoxicity Testing for
Pharmaceuticals;

89
 S Guideline

3. S3A – S3B Toxicokinetics and Pharmacokinetics

i. S3A Note for Guidance on Toxicokinetics: The Assessment of Systemic
Exposure in Toxicity Studies:
ii. S3A Q&As Question and Answers: Note for Guidance on Toxicokinetics: The
Assessment of Systemic Exposure – Focus on Micro sampling:

S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies:

90
 S Guideline
4. S4 Toxicity Testing
Duration of Chronic Toxicity Testing in Animals (Rodent and Non Rodent Toxicity
Testing):

S5 Reproductive Toxicology
S5(R2) Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to
Male Fertility:

S5(R3) Revision of S5 Guideline on Detection of Toxicity to Reproduction for Human

Pharmaceuticals:

91
 S Guideline
S6 Biotechnological Products
S6(R1) Preclinical Safety Evaluation of Biotechnology – Derived Pharmaceuticals:

S7A –S7B Pharmacology Studies

S7A Safety Pharmacology Studies for Human Pharmaceuticals:
S7B The Non clinical Evaluation of the Potential for Delayed Ventricular
Repolarization (QT Interval Prolongation) by Human Pharmaceuticals:
E14/S7B Q&As Question & Answers: Clinical and Non clinical Evaluation of
QT/QTc Interval Prolongation and Proarrhythmic Potential:
92
 S Guideline
S8 Immunotoxicology Studies
Immunotoxicity Studies for Human Pharmaceuticals:

S9 Non clinical Evaluation for Anticancer Pharmaceuticals

S9 Non clinical Evaluation for Anticancer Pharmaceuticals

S9 Q&As Question and Answer: Nonclinical Evaluation for Anticancer

Pharmaceuticals:
S10 Photosafety Evaluation
S10 Photosafety Evaluation of Pharmaceuticals: 93
 S Guideline
S11 Non clinical Paediatric Safety
S11 Nonclinical Safety Testing in Support of Development of Paediatric
Medicines:

94
 E Guideline
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/ pharmacogenomics techniques to produce better targeted
medicines.

95
 E Guideline
2.3.1 TYPE OF E GUIDELINE
1. E1 Clinical Safety for Drugs used in Long-Term Treatment
2. E2A - E2F Pharmacovigilance
3. E3 Clinical Study Reports
4. E4 Dose-Response Studies
5. E5 Ethnic Factors
6. E6 Good Clinical Practice
7. E7 Clinical Trials in Geriatric Population
8. E8 General Considerations for Clinical Trials
96
 E Guideline
9. E9 Statistical Principles for Clinical Trials
10. E10 Choice of Control Group in Clinical Trials
11. E11 - E11A Clinical Trials in Pediatric Population
12. E12 Clinical Evaluation by Therapeutic Category
13. E14 Clinical Evaluation of QT
14. E15 Definitions in Pharmacogenetics / Pharmacogenomics
15. E16 Qualification of Genomic Biomarkers
16. E17 Multi-Regional Clinical Trials
17. E18 Genomic Sampling
18. E19 Safety Data Collection
97
19. E20 Adaptive Clinical Trials
 E Guideline
E1 Clinical Safety for Drugs used in Long-Term Treatment
i. E1 The Extent of Population Exposure to Assess Clinical Safety for Drugs
Intended for Long-term Treatment of Non-Life Threatening Conditions:

2. E2A - E2F Pharmacovigilance

i. E2A Clinical Safety Data Management: Definition and Standards for Expedited
Reporting:
ii. E2B(R3) Clinical Safety Data Management: Data Element for Transmission of
individual Case safety Reports:
iii.E2B(R3) Q&As Implementation: Electronic Transmission of individual case safety
reports:
iv.E2C(R2) Periodic Benefit-Risk Evaluation Report:
v.E2C(R2) Q&As Question & Answer: Periodic Benefit- Risk Evaluation Reports:
98
 E Guideline

vi. E2D Post Approval Safety Data Management: Definitions and Standards for
Expedited Reporting:

vii.E2E Pharmacovigilance Planning:

viii. E2F Development Safety Update Reports:

99
 E Guideline
3. E3 Clinical Study Reports
i. E3 Structure and Content of Clinical Study Reports:

ii. E3 Q&As R1 Question and Answers: Structure and Content of Clinical Study
Reports:

4. E4 Dose-Response Studies
i. E4 Dose-Response Information to Support Drug Registration:

100
 E Guideline
5. E5 Ethnic Factors
E5(R1) Ethnic Factors in the Acceptability of Foreign Clinical Data:

6. E6 Good Clinical Practice

E6 (R2) Good Clinical Practice (GCP):

101
 E Guideline
7. E7 Clinical Trials in Geriatric Population
i. E7 Studies in Support of Special Populations: Geriatrics:

ii. E7 Q&As Question & Answer: Studies in Support of Special Populations:

Geriatric:

8. E8 General Considerations for Clinical Trials

i. E8 General Considerations for Clinical Trials:

ii. E8 (R1) Revision on General Consideration for Clinical Trials:

102
 E Guideline
9. E9 Statistical Principles for Clinical Trials
i. E9 Statistical Principles for Clinical Trials:

ii. E9 (R1) Addendum: Statistical Principles for Clinical Trials:

10. E10 Choice of Control Group in Clinical Trials

i. E10 Choice of Control Group and Related Issues in Clinical Trials:

11. E11 - E11A Clinical Trials in Pediatric Population

i. E11 (R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric
Population:

103
 E Guideline
ii. E11A Paediatric Extrapolation:

12. E12 Clinical Evaluation by Therapeutic Category

i. E12 Principles for Clinical Evaluation of New Antihypertensive Drugs:

104
 E Guideline

13. E14 Clinical Evaluation of QT

i. E14 The Clinical Evaluation of QT/Qtc Interval Prolongation and Proarrhythmic
Potential for Non-Antiarrhythmic Drugs
ii. E14 Q&As (R3) Question & Answer: The Clinical Evaluation of QT/QTc Interval
Prolongation and Proarrhythmic Potential for Non Antiarrhythmic Drugs
iii. E14/S7B Q&As Question & Answer: Clinical and Non clinical Evaluation of
QT/QTc Interval Prolongation and Proarrhythmic Potential

105
 E Guideline
14. E15 Definitions in Pharmacogenetics / Pharmacogenomics
i. E15 Definition for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics,
Genomic Data and Sample Coding Categories

E16 Qualification of Genomic Biomarkers

E16 Biomarkers Related to Drug or Biotechnology Product Development: Context,
Structure and Format of Qualification Submission

16. E17 Multi-Regional Clinical Trials

E17 General principle for planning and design of Multi Regional Clinical Trials

106
 E Guideline

17. E18 Genomic Sampling

E18 Genomic Sampling and Management of Genomic Data

18. E19 Safety Data Collection

E19 Optimization of Safety Data Collection

19. E20 Adaptive Clinical Trials

E20 Adaptive Clinical Trials

107
 M Guideline
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).

108
 M Guideline
2.4.1 TYPE OF M GUIDELINE:
1. M1 MedDRA Terminology
2. M2 Electronic Standards
3. M3 Nonclinical Safety Studies
4. M4 Common Technical Document
5. M5 Data Elements and Standards for Drug Dictionaries
6. M6 Gene Therapy
7. M7 Mutagenic impurities
8. M8 Electronic Common Technical Document (eCTD)
9. M9 Biopharmaceutics Classification System-based Biowaivers
10. M10 Bioanalytical Method Validation
11. M11 Clinical electronic Structured Harmonised Protocol (CeSHarP)
12. M12 Drug Interaction Studies
109
 M Guideline

1. M1 MedDRA Terminology
i. MedDRA Medical Dictionary for Regulatory Activities:

2. M2 Electronic Standards
i. ESTRI Electronic Standards for the Transfer of Regulatory Information:

3. M3 Nonclinical Safety Studies

i. M3 (R2) Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical
Trials and Marketing Authorization for Pharmaceuticals:

110
 M Guideline
ii. M3 (R2) Q&As R2 Question & Answers: Guidance on Non clinical Safety Studies
for the conduct of Human Clinical Trials and Marketing Authorization for
Pharmaceuticals:

4. M4 Common Technical Document

i. CTD The Common Technical Document:

6. M6 Gene Therapy
i. M6 Virus and Gene Therapy Vector Shedding and Transmission:

111
 M Guideline

7. M7 Mutagenic impurities
i. M7 (R1) Assessment and Control of DNA Reactive Impurities in
Pharmaceuticals to limit Potential Carcinogenic risk:

ii. M7 (R2) Assessment and Control of DNA Reactive Impurities in

Pharmaceuticals to limit Potential Carcinogenic risk:

8. M8 Electronic Common Technical Document (eCTD)

i. Electronic Common Technical Document:

112
 M Guideline

9. M9 Biopharmaceutics Classification System-based Biowaivers

10. M10 Bioanalytical Method Validation

11. M11 Clinical electronic Structured Harmonised Protocol (CeSHarP)

12. M12 Drug Interaction Studies

113