Transcript Brief Introduction to General Requirements of Health

1. History
 From the beginnings of civilization people
have been concerned about the quality and
safety of foods and medicines.
 Regulation of food in the United States dates
from early colonial times.
 Federal controls over the drug supply began
with inspection of imported drugs in 1848.
3
S.S.P.C.
Cont…
Year
Events occurred
1820
U.S. Pharmacopoeia
1848
Drug importation act
1883
Bureau of chemistry's food adulteration studies
1907
Certified color regulations
1939
First food standards
1949
Guidance to industry on procedures for the appraisal of the toxicity of chemicals in food
1954
Radiological examination of food
1966
Child protection act
1971
National center for toxicological research
1976
Medical device amendments
1982
Tamper-resistant packing regulations
1994
Dietary supplement health and education act
2004
Food allergy labeling and consumer protection act
2005
Drug safety board
4
S.S.P.C.
2. What is the need?
5
S.S.P.C.
3. FDA Objective
Better
consumer
information.
Post
marketing
safety
Counter
terrorism
New
product
review
Keep
watch on
safe
manufacturing
and handling
Monitoring
for
new risk
Standard
and
regulation
Enforcement
&
correcting
problem
6
S.S.P.C.
In short,
 To promote and protect the public health by
helping safe and effective products reach the
market in a timely way.
 To monitor products for continued safety
after they are in use, and
 To help the public get the accurate, sciencebased information needed to improve health
7
S.S.P.C.
4. FDA Components
CBER
CDRH
CDER
CFSAN
CVM
NCTR
OC
ORA
COSMETICS
8
Cont…
S.S.P.C.
Sr.
No
Componen
t
Full Form
Regulates
5A
CBER
Center For Biologics
Evaluation And
Research
Biological Products
5B
CDRH
Center For Devices And
Radiological Health
Safety and Effectiveness of New Medical Devices Before they are
Marketed
5C
CDER
Center For Drug
Evaluation And
Research
Health of by Assuring Prescription and OTC Drugs are Safe and
Effective
5D
CSFAN
Center For Food Safety
And Applied Nutrition
Food Supply is Safe, Sanitary, Wholesome, and Honestly Labeled,
and Cosmetic Products are Safe and Properly Labeled.
5E
CVM
Center For Veterinary
Medicine
Assure that Animal Food Products are Safe.
5F
NCTR
National Center For
Toxicological Research
Human Toxicity
5G
OC
Office Of The
Commissioner
5H
ORA
Office Of Regulatory
Affairs
Products Comply with Appropriate Public Health Laws and
Regulations.
9
4A. CBER
S.S.P.C.
 CBER regulates biological products to advancing the
public health through innovative regulations that
ensure the safety
 effectiveness and
 timely delivery to patients of biological
products.
 Current authority for this responsibility resides in
Section 351 of the Public Health Service Act and in
specific sections of the Food Drug and Cosmetic Act.
 The mission of CBER is to protect and enhance the
public health through the regulation of biological
and related products including blood, vaccines,
tissue, allergenic and biological therapeutics.
10
S.S.P.C.
4B. CDRH
CDRH assure that new medical
devices are safe and effective before
they are marketed.
Surgical Tools
Prevent
Diagnose
or Treat
Monitors Devices
Throughout the
Product Life Cycle,
Including
Postmarketing
Surveillance System
Radiation
Emitting
Products
11
S.S.P.C.
4C. CDER
 The FDA's Center for Drug Evaluation and
Research (CDER) promotes and protects the
health,
• by assuring that all prescription and
• over-the-counter drugs are safe and effective.
 CDER evaluates all new drugs before they
are sold, and serves as a consumer guide for
the more than 10,000 drugs on the market to
be sure they continue to meet the highest
standards.
12
S.S.P.C.
4D. CFSAN
 The Center for Food Safety and Applied Nutrition,
known as CFSAN, is one of six product-oriented
centers, in addition to a nationwide field force, that
carry out the mission of the Food and Drug
Administration (FDA).
 The mission of CFSAN is, promoting and protecting
•
•
•
•
•
the public's health by ensuring that the nation's food
supply is
safe,
sanitary,
wholesome, and
honestly labeled, and
that cosmetic products are safe and properly labeled.
 Scope as follow,
13
Cont…
S.S.P.C.
1.
The safety of substances added to food, like food and
2.
3.
4.
5.
6.
7.
8.
9.
color additives.
The safety of foods and ingred. developed through
biotechnology.
Seafood hazard analysis and critical control point
(HACCP) regulations.
Health risks associated with food borne chemical, and
biological contaminants.
Regulations and activities dealing with the proper
labeling of foods and cosmetics.
Policy governing the safety of dietary supplements,
infant formulas, and medical foods.
Food industry postmarketing surveillance and
compliance.
Consumer education and industry outreach.
Cooperative programs with state and local
governments.
14
Cont…
S.S.P.C.
 Some of CFSAN's current areas of food safety concern
are:
biological pathogens (e.g., bacteria, viruses, parasites)
naturally occurring toxins (e.g., mycotoxins, ciguatera
toxin, paralytic shellfish poison)
3.
dietary supplements (e.g., ephedra)
4.
pesticide residues
5.
toxic metals (e.g., lead, mercury)
6.
decomposition and filth (e.g., insect fragments)
7.
food allergens (e.g., eggs, peanuts, wheat, milk)
8.
nutrient concerns (e.g., vitamin D overdose, pediatric
iron toxicity)
9.
dietary components (e.g., fat, cholesterol)
10. radionuclide
11. product tampering
1.
2.
15
4E. CVM
S.S.P.C.
 The FDA's Center for Veterinary Medicine (CVM) evaluates the
safety and effectiveness of drugs used to treat animals.
 Nearly 300 drugs currently on the market have been approved
by the FDA for dogs, cats and horses.
 CVM has two top priorities:
1. Prevent the establishment of bovine spongiform
encephalopathy (BSE), "mad cow disease." &
2. Counter the risk of antibiotic resistance in humans from animal
food.
 CVM regulates the manufacture and distribution of food
additives and drugs that will be given to animals.
 CVM is responsible for regulating drugs, devices, and food
additives given to animals like poultry, cattle, swine, and
minor animal species (other than cattle, swine, chickens,
turkeys, horses, dogs, and cats).
16
S.S.P.C.
4F. NCTR

All of the research performed at the National
Center for Toxicological Research is targeted to
fulfill three strategic research goals in support of
FDA's public health mission.
1.
Risk Assessment for Regulated Products
2.
Knowledge Bases that Predict Human Toxicity
3.
Methods use for FDA Standard Development and
Product Risk Surveillance

NCTR includes,
Centre of Excellence
Research Division
17
Cont…
S.S.P.C.
NCTR
Centre of
Excellence
Toxico
informatics
Photo
toxicology
Functional
Genomics
Structural
Genomics
Hepato
toxicology
Metabolomics
Proteomics
18
Cont…
S.S.P.C.
NCTR
Research Division
Biometry and
Risk Assessment
Systems
Toxicology
Veterinary
Services
Biochemical
Toxicology
Genetic and
Reproductive
Toxicology
Microbiology
Molecular
Epidemiology
Neurotoxicology
19
4G. OC
S.S.P.C.
The Office of the Commissioner is made up of several
components,
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Ethics Program
Good Clinical Practice Program
History Office
Office of Combination Products
Office of Crisis Management
Office of Equal Employment Opportunity and Diversity Management
Office of Financial Management
Office of International Programs
Office of the Ombudsman
Office of Orphan Products Development
Office of Pediatric Therapeutics
Office of Planning
Office of Policy
Office of Public Affairs
Office of Special Health Issues
Office of Women's Health
Small Business Program
20
4H. ORA
S.S.P.C.
 to ensure that FDA regulated products comply with
appropriate public health laws and regulations.
 Compliance Strategies of ORA includes,
• Providing information to industry
• Highlighting areas of significant violations and impact on
public health
• Prioritizing and targeting high-risk areas
• Cooperating with state and local public health authorities and
regulators
• Focusing on covering products imported into the US through
border coverage and foreign inspections.
21
4I. COSMETICS
S.S.P.C.
 FDA is only able to regulate cosmetics after
products are released to the marketplace.
 Neither cosmetic products nor cosmetic ingredients
(except color additives) are reviewed or approved
by FDA before they are sold to the public.
 Includes,
I.
Animal Testing for Cosmetic Products
II. Inspection of Cosmetics
III. Shelf life
IV. Federal Food, Drug, and Cosmetic Act (FD&C Act)
and
V. Fair Packaging and Labeling Act (FPLA)
22
I. Animal Testing for Cosmetic Products
S.S.P.C.
 FDA does not mandate to do animal
testing
 FDA develop validated alternatives to
animal testing in assessing cosmetic safety
23
S.S.P.C.
II. Inspection of Cosmetics
 An investigator may look for the following,
1. Use of prohibited ingredients
2. Improper use of restricted ingredients
noncompliance with requirements related to
color additives
3. Microbial contamination
4. Failure to adhere to requirements for
tamper-resistant packaging
5. Deficiencies in labeling and packaging
24
S.S.P.C.
III. Shelf Life
 No regulations or requirements under
current united states law
 Manufacturers have the responsibility to
determine shelf life for products
25
S.S.P.C.
IV. Cosmetic Labeling
 The name of manufacturer, packer or
distributor
 Place of business of the manufacturer,
packer or distributor
 An accurate statement of the quantity of
contents
 Any appropriate directions for safe use
and
 Warning statements
26
S.S.P.C.
5. FDA Mission
Mission
Statement
FDA
Strategic
Plan
FDA
Customer
Service
Standards
What
FDA
Regulates
What
FDA
Does
Not
Regulate
Laws
Enforced
By
FDA
27
S.S.P.C.
5A. MISSION STATEMENT
 The FDA is responsible for protecting the public health by






assuring the safety, efficacy, and security of
human and veterinary drugs,
biological products,
medical devices,
our nation’s food supply,
cosmetics, and
products that emit radiation.
 The FDA is also responsible for advancing the public health by
helping to speed innovations that make medicines and foods
more effective, safer, and affordable.
 And helping the public to get the accurate, science-based
information they need to use medicines and foods to improve
their health.
28
S.S.P.C.
5B. FDA STRATEGIC PLAN
Efficient
Risk
Management
More Effective
Regulation
Through a
Stronger
Workforce
Improving
Health
Through Better
Information
PLAN
Protecting
America
From Terrorism
Improving
Patient and
Consumer
Safety
29
I. Efficient Risk Management
S.S.P.C.
 Use science-based, efficient risk management
in all agency regulatory activities, so that the
agency's limited resources can provide the
most health promotion and protection at the
least cost for the public.
 The Most Public Health risk for Regulatory
are at the time of,
1. Enforcement: Targeting Limited Resources for Maximum
2.
3.
4.
5.
Protection
New Drug Development.
Manufacturing.
Imports.
Foods: Foodborne Disease Remains a Major Public Health
Threat
30
Cont…
S.S.P.C.
Maximum liable areas
for Risk
Design
Process
Materials
Facilities
Manufacturing
Distribution
Patient
31
S.S.P.C.
Cont…
 Objective 1 -- Provide timely, high quality, cost-effective
process for review of new technologies / premarket
submissions.
 Objective 2 -- Provide high quality, cost-effective
oversight of industry manufacturing, processing and
distribution to reduce risk.
 Objective 3 -- Assure the safety of the U.S. food and
cosmetics supply to protect consumers at the least cost for
the public.
 Objective 4 -- Develop methodological strategies and
analyses to evaluate options, identify the most effective
and efficient risk management strategies, and optimize
regulatory decision-making.
32
II. Improving Health Through Better Information
S.S.P.C.
 Empowering Consumers: Improving Health
Through Better Information able consumers about
the benefits and risks of FDA-regulated products.
 Objective 1 – Develop an FDA-wide consumer
communications infrastructure.
 Objective 2 – Enhance the FDA's efforts to help
ensure that industry communications to consumers
and health care providers
1. are truthful and not misleading,
2. provide information about product risks and benefits, and
3. appropriately convey the degree of scientific uncertainty
associated with such product messages.
33
III. Improving Patient And Consumer Safety
S.S.P.C.
 Objective 1. Enhance the ability to quickly identify risks associated with FDA-
regulated products.
 Objective 2. Increase capacity to accurately analyze risks associated with
medical products, dietary supplements, and foods.
 Objective 3. Take appropriate actions to communicate risks and correct
problems associated with medical products, dietary supplements and foods.
 Objective 4. The FDA must uphold its responsibility for ensuring the safety of
approximately 80 percent of the nation's food supply.
 Objective 5. Protect the safety and security of human drugs, biologics (vaccines,
blood and blood products, gene therapy, human tissues, and cellular therapies),
medical devices (including radiation-emitting and screening devices),
veterinary drugs, and other FDA-regulated products.
34
IV. Protecting America From Terrorism
S.S.P.C.
 Objective 1. Facilitate the development and
availability of medical countermeasures to limit the
effects of a terrorist attack on the civilian or military
populations.
 Objective 2. Enhance the agency's emergency
preparedness and response capabilities to be better
able to respond in the event of a terrorist attack.
 Objective 3. Ensure the safety and security of FDA
personnel, physical assets, and sensitive information.
35
V. More Effective Regulation Through a Stronger Workforce
S.S.P.C.
 Ensure a world-class professional workforce, effective and efficient
operations, and adequate resources to accomplish the agency's
mission.
 Objective 1 -- Ensure a high quality, diverse and motivated
workforce.
 Objective 2 -- Increase efficiency and effectiveness of agency
management.
 Objective 3 -- Ensure effective communication and working
relationships with key external stakeholders to enhance U.S. and
global health outcomes.
 Objective 4 -- Transition Information technology from an enabler to
a strategic tool for realizing the FDA's policy goals and objectives.
 Objective 5 -- Provide a consolidated FDA headquarters campus to
improve operations for employees.
36
5C. FDA CUSTOMER SERVICE STANDARDS
S.S.P.C.
I.
Customers
II.
Health professionals
III.
Regulated industry
IV.
Other government agencies
37
S.S.P.C.
I. Customers
1. Fair, courteous and professional treatment,
2. Information that is accurate and current,
3. Timely responses to requests,
4. Reasonable access to appropriate staff,
5. Confidence that efforts are made to assure that regulated products
in the marketplace are in compliance with FDA laws and
regulations,
6. Two-way communication,
7. Opportunities for collaboration and partnerships, as appropriate,
8. Participation in the agency's decision-making process
9. Accurate and timely health information about regulated products
38
S.S.P.C.
II. Health Professionals
 Timely information that will assist them in
advancing and protecting the public health
39
S.S.P.C.
III. Regulated Industry
 Timely review of product applications,
 Professional treatment in resolving disputes,
 Fair application of laws and regulations in
enforcement activities,
 Fair and consistent inspections and product
application reviews,
 Respect in the agency's performance of duties
and responsibilities.
40
S.S.P.C.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
5D. WHAT FDA REGULATES
Biologics
Product and manufacturing establishment licensing
Safety of the nation's blood supply
Research to establish product standards and develop
improved testing methods
Cosmetics
Safety
Labeling
Drugs
Product approvals
OTC and prescription drug labeling
Drug manufacturing standards
Foods
41
S.S.P.C.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Cont…
Safety of all food products (except meat and poultry)
Bottled water
Medical devices
Premarket approval of new devices
Manufacturing and performance standards
Tracking reports of device malfunctioning and serious
adverse reactions
Radiation-emitting electronic products
Radiation safety performance standards for microwave
ovens, television receivers, diagnostic
X-ray equipment, cabinet x-ray systems (such as baggage xrays at airports), laser products,
Ultrasonic therapy equipment, mercury vapor lamps, and
sunlamps
Accrediting and inspecting mammography facilities
Veterinary products
42
S.S.P.C.
25. GMP
 Building and Facilities
 Equipment
 Personnel
 Raw materials
 Production
 Laboratory controls
 Records
 Labeling
 Complaints
 Other
43
S.S.P.C.
Cont…

GMP Workshop in July 2003: 5 year vision:
“Develop a harmonised pharmaceutical quality system
applicable across the life cycle of the product
emphasizing an integrated approach to quality risk
management and science”

Consequent ICH Expert Working Groups (EWG):
1.
ICH Q8, on Pharmaceutical Development, doc. approved
Nov. 2005
ICH Q9, on Quality Risk Management, doc. approved Nov.
2005
ICH Q10, on Quality Systems, topic accepted 2005
2.
3.
44
Low
Low
m
pr
ov
e
im
co
nt
in
ua
l
Risk from Manufacturing
site
High
Q10 Pharm. Quality Systems
S.S.P.C.
en
t
Concluding…
Q8 Pharmaceutical Development
High
Product / Process Risk
45
5E. WHAT FDA DOES NOT REGULATE
S.S.P.C.
 Advertising
 Alcohol
 Consumer Products
 Drugs of Abuse
 Health Insurance
 Meat and Poultry
 Pesticides
 Restaurants and Grocery Stores
 Water
46
5F. LAWS ENFORCED BY FDA
S.S.P.C.
1.
Federal Food, Drug and Cosmetic Act
2.
Food and Drug Administration Modernization Act (FDAMA)
3.
Infant Formula Act of 1980
4.
Orphan Drug Act
5.
Drug Price Competition and Patent Term Restoration Act of 1984
6.
Medical Device Amendments of 1992
7.
Prescription Drug User Fee Act (PDUFA) of 1992
8.
Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994
9.
Dietary Supplement Health and Education Act of 1994
10.
Food and Drug Administration Modernization Act (FDAMA) of 1997
11.
Best Pharmaceuticals for Children Act
47
Cont…
S.S.P.C.
12.
Medical Device User Fee and Modernization Act (MDUFMA) of 2002
13.
Animal Drug User Fee Act of 2003 PDF
14.
Minor Use and Minor Species Animal Health Act of 2004
15.
Food Allergen Labeling and Consumer Protection Act of 2004
16.
Federal Anti-Tampering Act
17.
Sanitary Food Transportation Act
18.
Mammography Quality Standards Act (MQSA)
19.
Bioterrorism Act of 2002
20.
Public Health Service Act
21.
Trademark Act of 1946
22.
Controlled Substances Import and Export Act
48
S.S.P.C.
6. FDA Activities
1.
Broad Responsibilities
8.
Safe and Effective Animal Drugs
2.
Benefits Vs. Risks
9.
Standards and Regulations
3.
Safe, Wholesome and Sanitary Food
10. Science, Regulation and Consumer
Protection
4.
Safe and Effective Medicine,
Biological and Medicinal Device
5.
Safe Consumer and Medicinal
Radiation Products
6.
7.
Truthful and Informational Labels
Safe Cosmetics
11. Keeping Watch
12. Safe Manufacturing and Handling
13. Monitor for New Risks
14. Research
15. Enforcements
49
S.S.P.C.
7. Information for Others
 Consumers
 Press
 Patients (HIV and AIDS Activities)
 Women (Guide to Pregnancy
 Health Professionals
(Clinical Trials, Dietary Supplements &
Drugs)
 Health Educators (Latest FDA
medical product and health news
)
 State/Local Officials
 Industry
Registries Menopausal Hormone
Initiative
)
 FDA Alumni
 Seniors
 Teens (Birth control guide, Tobacco
)
information
 Kids (Food Safety Quiz, Match the
)
pair
50
S.S.P.C.
8. What is New ?
MISCELLANEOUS
DRUGS
MEDICAL
DEVICES
FOOD
51
Cont…
S.S.P.C.
DRUGS
 Antidepressant Use in










Children, Adolescents, and
Adults
Buying Medicines Online
Celexa
Cialis
Counterfeit Drugs
COX-2 Inhibitors (Vioxx,
Bextra, Celebrex...)
Foreign Rx Drugs
Oxycontin
Phenylpropanolamine (PPA)
Protonix
Viagra
FOODS












E. coli East Coast Outbreaks
Spinach/E. coli Information
Food Safety for Moms-to-Be
Food Guide Pyramid
Hurricane and Food Safety
Bioengineered Foods
Color Additives
Foodborne Illness
Holiday Food Safety
Konjac Candy Recalls
Mercury in Fish
Dietary Supplements
52
S.S.P.C.
Cont…
MEDICAL DEVICES
 Contact Lenses and Eye








Infections
Decorative Contact Lenses
Breast Implants
Device User Fees
LASIK Eye Surgery
Tampons
Radiation Protection
Whole Body CT Scans
Wireless (Cell) Phones
MISCELLANEOUS

















Animal Cloning
Antibiotic Resistance
Bioterrorism Act
BSE (Mad Cow Disease)
Buying Medical Products Online
Cosmetics
Counterterrorism
Flu Information
Poison Ivy
Halloween Safety Tips
Heart Health
Losing Weight
Marijuana for Medical Use
Quitting Smoking
SARS
Tattoos
White Oak
53
S.S.P.C.
9. Challenges faced by FDA
 Scientific breakthroughs
 More sophisticated products
 New public health threats
 International commerce
 Consumer information
54
S.S.P.C.
10. Reference
55
SEMINAR ON….
56
Home page of TGA
57
About TGA
TGA is an unit of the Australian
Government Dept. of Health & Ageing.
Carries out assessment and monitoring
activities over Therapeutic goods.
To ensure that Australian community has
an access, within a reasonable time, to
advanced therapeutics.
58
The TGA regulates therapeutic products
through:
pre-market assessment;
post-market monitoring and enforcement of
compliance with standards; and licensing of
Australian manufacturers and verifying
overseas manufacturers' compliance with
the same standards as their Australian
counterparts.
59
Activities undertaken by TGA
The regulation of therapeutic goods
Committees
Online services
Consultation documents
Tenders
Recruitment
Laboratories
TGA news
International activities
60
International activities
Management and coordination of advisory and
training services for regulatory matters.
TGA integrates its activities with similar projects
initiated by Food Standards Australia New
Zealand (FSANZ) and co-ordinate TGA’s
therapeutics regulation with New Zealand.
61
International activities
International agreements
WHO Collaborating Centers
TGA international training information
TGA retroviral medicines
62
Blood and tissues
Blood,
Blood components,
Plasma derivatives,
Tissue and cellular products, and
Tissue cell based derivatives
Regulated under the Therapeutic Goods
Act 1989.
63
Blood and tissues
Regulation of blood
Regulation of tissues
Consultation documents
Committees
Global Collaboration for Blood Safety
Export of human blood, tissues, related
materials
International agreements
64
Chemicals
The Office of Chemical Safety undertakes the
risk assessment and provides advice on
potential public health risks posed by chemicals
used in community.
Example includes : Cosmetics, Agricultural,
Veterinary, Industrial Chemicals, Pesticides.
65
Chemicals
Regulation of chemicals
Agricultural and veterinary
chemicals
Environmental chemical issues
Committees
Cosmetic claim guidelines
Consultation documents
66
Committees
Australian drug evaluation committee
(ADEC)
 Adverse Drug Reaction Advisory Committee
(ADRAC)
 Complementary Medicines Evaluation
Committee (CMEC)
 Medical Device Evaluation Committee
(MDEC)
 Medicines Evaluation Committee (MEC)
67
Committees
 National Coordinating Committee on
Therapeutic Goods (NCCTG)
 National Drugs and Poisons Schedule
Committee (NDPSC)
 Therapeutic Goods Committee (TGC)
 Australian Influenza Advisory Committee
(AIVC)
 Gene technology committees
68
Australian drug evaluation
committee (ADEC)
Advises the minister or the secretary on
medical and scientific evaluations of drugs and on
the timely availability of new therapeutic
advances in Australia.
69
Adverse Drug Reaction Advisory
Committee (ADRAC)
Subcommittee of ADEC.
Reviews reports of adverse reactions to
medicines and vaccines.
70
Medical Device Evaluation
Committee (MDEC)
 Provides independent medical and scientific
advice to the Minister and TGA on the safety,
quality and performance of medical devices
supplied in Australia.
 Pre-marketing and post-marketing monitoring.
71
Medicines Evaluation Committee
(MEC)
Advices the Minister and Secretary on
matters relating to the registration of
Over-the-counter (OTC) medicines.
72
Therapeutic Goods Committee
(TGC)
• An expert committee which advises the
Minister for Health and Ageing on
adoption of therapeutic standards,
requirements for labeling/packaging and
the manufacturing principles.
73
Complementary medicines
• Complementary medicines are also known
as ‘traditional’ or ‘alternative’ medicines.
• Examples include vitamins, minerals,
nutritional supplements and herbal,
aromatherapy and homeopathic products.
74
Complementary medicines
• Regulation of complementary
medicines
• Information for sponsors
• Forms
• Guidelines
• Hints, tips and other information
• Electronic listing facility (ELF)
75
Complementary Medicines
Evaluation Committee (CMEC)
Advise to the TGA’s office of complementary
medicines on whether a new complementary
substance or medicine should be permitted in the
ARTG as a listed or registered product
76
Gene technology
• The Gene Technology Act 2000
introduces a national scheme for the
regulation of genetically modified
organisms in Australia to protect the
health and safety of Australians and the
Australian environment.
77
Gene technology
• Regulation of gene technology
• Policy principles
• Record of genetically modified products
• Consultation documents
• Committees
78
Gene technology committees
Gene Technology Ministerial Council( GTMC)
A commonwealth, state and territory council established by the
intergovernmental Gene Technology Agreement 2001
Gene Technology Standing Committee (GTSC)
Provides high level support to the Gene Technology Ministerial
Council
Gene Technology Technical Advisory Committee (GTTAC)
A statutory advisory committee which takes the place of GMAC
and provides scientific and technical advice to the Gene
Technology Regulator and the Gene Technology Ministerial
council.
79
Over-the-counter medicines
Can buy OTC medicines for self-treatment from
pharmacies, with selected products also available in
supermarkets, health food stores and other retailers.
Ex. includes
 cough and cold remedies
 anti fungal treatments
 sunscreens
 Non-prescription analgesics such as aspirin,
PCM
80
Over-the-counter medicines
Regulation of OTC medicines
OTC medicines electronics lodgement system
Advertising therapeutic goods
Medicines labeling review
Information for sponsors
 Forms
 Guidelines
 Hints, tips &other information
81
Manufacturing
• In most cases manufacturers of
therapeutic goods must hold a license.
• To obtain a license to manufacture
therapeutic goods, a manufacturer must
demonstrate, during a factory audit,
compliance with manufacturing principles
which include codes of good
manufacturing practice.
82
Manufacturing
•
•
•
•
•
•
•
•
Codes of good manufacturing practice
Manufacturing guidelines
Manufacturing principles
Online services
Forms for manufacturers
Australian manufacturers
Overseas manufacturers
International agreements
83
Australian Code of
GMP for Medicinal
Products
84
Australian code of GMP for
medicinal products
includes 9 chapters.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Quality Management
Personnel
Premises and Equipment
Documentation
Production
Quality control
Contract Manufacture and Analysis
Complaints and Product Recall
Self Inspection
85
ANNEXES
Annex 1 Manufacture of sterile medicinal products
Annex 2 Manufacture of biological medicinal products
for human use
Annex 3 Manufacture of radiopharmaceuticals
Annex 4 Manufacture of veterinary medicinal products
other than immunologicals
Annex 5 Manufacture of immunological veterinary
medical products
Annex 6 Manufacture of medicinal gases
86
ANNEXES
Annex 7 Manufacture of herbal medicinal products
Annex 8 Sampling of starting and packaging materials
Annex 9 Manufacture of liquids, creams and ointments
Annex 10 Manufacture of pressurized metered dose
aerosol preparations for inhalation
Annex 11 Computerized systems
Annex 12 Use of ionizing radiation in the manufacture
of medicinal products
87
ANNEXES
Annex 13 Manufacture of investigational medicinal
products
Annex 14 Manufacture of products derived from human
blood or human plasma
Annex 15 Qualification and validation
Annex 16 Qualified person and batch release
Annex 17 Parametric release
Annex 18 GMP guide for Active Pharmaceutical
Ingredients
88
Guidelines on Standard of
Overseas Manufacturers
• Intended to provide information on– What is regarded by the TGA as an
acceptable form of evidence
– Guidance for sponsors and
manufacturers on the submission of
that evidence to the TGA for
assessment.
89
• Evidence of the standard of manufacture submitted
will be reviewed by the Manufacturer Assessment
Section (MAS) of the TGA.
• Current sponsors of therapeutic goods manufactured
outside Australia will be requested on periodic basis
to provide evidence that the standard of
manufacture of those therapeutic goods continues to
be acceptable.
90
• Failure to supply this information may result in the
product’s registration/listing being cancelled
(Therapeutic Goods Act 1989 Subsection 30(2)(c))
• Sponsors should also note that TGA reserves the
right to request an audit (inspection) of any
overseas facility.
91
References
www.tga.gov.au.
92
Seminar on:
WHO GUIDELINES
(Under Global Regulatory
Requirements)
INTRODUCTION
 The World Health Organization is the United
Nations specialized agency for health.
 It was established on 7 April 1948.
 WHO is governed by 192 Member States through the




World Health Assembly .
All countries which are Members of the United
Nations may become members of WHO
The Executive Board is composed of 32 members
technically qualified in the field of health.
Members are elected for three-years.
The Organization is headed by the Director-General,
who is appointed by the Health Assembly on the
nomination of the Executive Board.
94
•Regional offices are in•Africa, America, Southeast Asia, Europe, Eastern Mediterranean,
Western Pacific
95
 WHO has four main
 WHO RESEARCH
 To give worldwide
 WHOLIS- World health
functions:
guidance in the field of
health
 To set global standards
for health
 To cooperate with
governments in
strengthening national
health programs
TOOLS INCLUDE-
organization database
available on net, all
publication since 1948
 WHOSIS-A guide to
epidemiological and
statistical information
available from WHO.
 To develop and transfer
appropriate health
technology information
96
WHO stability guidelines
 “Guidelines for stability testing of
pharmaceutical products containing well
established drug substances in
conventional dosage forms”
 It is for the stability testing of final drug
products that are well established (e.g.
generics) and are in conventional dosage
forms (e.g. tablets).
97
 The storage conditions recommended by
manufacturers on the basis of stability studies
should guarantee the maintenance of quality,
safety, and efficacy throughout the shelf-life of a
product.
 The effect of the extremely adverse climatic
conditions existing in certain countries to which
they may be exported calls for special
consideration.
 In a stability study, the effect of variations in
temperature, time, humidity, light intensity and
partial vapor pressure are investigated.
98
 For reconstituted product : “in use” stability
data must be submitted to support the
recommended storage time and conditions.
 Four climatic zones can be distinguished for
the purpose of worldwide stability testing, as
follows:
• Zone I: Temperate.
• Zone II: Subtropical, with possible High
Humidity.
• Zone III: Hot/Dry.
• Zone IV: Hot/Humid.
99
Design of stability studies
Test samples
1) For registration purposes, test samples of products
should contain fairly stable active ingredients and
should be from two different production batches.
2) Should be representative of the manufacturing process.
3) Should be manufactured from different batches of API,
if possible.
4) Suggested sampling schedule :
- - One batch every other year for formulations considered
to be stable, otherwise one batch per year;
- - One batch every 3-5 years for formulations for which
the stability profile has been established, unless a major
change has been made
100
Test conditions
Accelerated
studies
Less stable
Zone 2
6 months
stable
Zone 2
3 months
Zone 4
6 months
101
Alternative Storage condition :
1) Storage for 6 months at a temp of at least 15 °C above
the expected actual storage temp & appropriate RH.
2) Storage at higher temp may also be recommended, e.g.
3 months at 45-50 °C and 75% relative humidity (RH) for
zone IV.
3) Where significant changes occur in the course of
accelerated studies, additional tests at intermediate
conditions should be conducted, e.g. 30 ± 2 °C and 60 ±
5% RH.
 Real-time studies
For registration purposes, the results of real time studies
of at least 6 months' duration should be available at the
time of registration.
102
Frequency of testing and evaluation of
test results
 For accelerated studies: 0, 1, 2, 3 and, when
appropriate, 6 months;
 For real-time studies: 0, 6 and 12 months, and then
once a year.
 For on-going studies:
For the confirmation of the provisional shelf-life: 6months
For well established products : 12 months
 Highly stable formulations : first 12 months and
then at the end of the shelf-life.
 Less stable drug substances : every 3 months in the
first year, every 6 months in the second year, and
then annually
103
 Analytical methods
-Analytical methods should be validated or verified
-All product characteristics likely to be affected by storage
should be determined
-Tests for related compounds or products of
decomposition should also be validated.
 Stability report: Provides details of the design of the
study, as well as the results and conclusions
104
WHO Guidelines on Sampling of
Pharmaceuticals
105
Sampling comprises of the operations designed to select a
portion of a material for a defined purpose. All operations
related to sampling should be performed with care, using
proper equipment and tools
prequalification
acceptance of
consignments
Purpose
Of sampling
inspection for
customs clearance,
deterioration,
adulteration, etc.;
in-process
control
106
Starting
materials
Pharmaceutical
products
Classes and
Types of
Materials
Pri. and sec.
packaging
materials
Intermediates
Controls to be applied to the sample may be:
- checking the identity of a material;
- performing complete pharmacopoeial or analogous testing;
- performing special/specific tests.
107
Sampling operation and precautions
- Procedure should be such that any non-uniformity of the
material can be detected
- Non-homogeneous portions of the material or bulk should be
sampled and tested separately
- Compositing of the samples from the diff. portions should be
avoided, since it can mask contamination
For Finished drug products the sampling procedure must take
account
- Official and non-official tests ( for dosage forms)
- Non-official tests could include testing for adulteration,
counterfeiting, etc.
108
STORAGE AND RETENTION
- Container used to store a sample shouldn’t interact with the
sampled material nor allow contamination, should protect from
light, air, moisture, etc., as req. by the storage directions for the
material sampled
- Samples should be stored in accordance with the storage
conditions as specified for the respective API, excipient or drug
product
 Closures and labels should be preferably of such a kind that
unauthorized opening can be detected.
- Samples must never be returned to the bulk.
109
SAMPLING FOR REGULATORY
PURPOSES
- Additional samples for regulatory testing and verification
purposes should be provided (e.g. duplicate testing and
parallel testing by different regulatory laboratories and by
the consignee of the product)
110
SAMPLING PLANS FOR STARTING
MATERIALS, PACKAGING MATERIALS
AND FINISHED PRODUCTS
STARTING MATERIAL:
The “n plan”
Used only when material
1) is uniform &
2) supplied from a recognized source
FORMULA :
n = 1+√N
Where, N is the number of sampling units
According to this plan, original samples are taken from N
sampling units selected at random
n-plan is not statistically based and should be used only as a
guiding principle.
111
The “r plan”
Used when material
1) is non-uniform &
2) supplied from source that is not well known
FORMULA :
r = 1.5√N
Where, N is the number of sampling units
According to this plan samples are taken from each of the N
sampling units of the consignment and placed in separate sample
containers & tested.
If the results are in agreement, r final samples are formed by
appropriate pooling of the original samples.
If these results are in agreement, the r samples are combined for
the retention sample.
112
GUIDELINES ON
GOOD MANUFACTURING PRACTICES (GMP):
VALIDATION
 Focuses mainly on the overall concept of validation and is intended
as a basic guide for use by GMP inspectors.
 It encompasses details related to :Validation; Qualification ;
Calibration and verification
Other aspects addressed in this guideline include the Validation
Team, Validation Master Plan, Validation Protocol (VP), Validation
Report (VR), types of validation, Re-validation and Change Control
associated with validation.
113
WHO’s guidelines on- INSPECTION

Inspection of…..
pharmaceutical manufacturers
drug distribution channels (products)

Guidelines for pre-approval inspection
Quality system requirements for national GMP
Inspectorates

-Intended
to
pharmaceutical
Member States
promote
harmonization
of
inspection practices among WHO
114
Objectives
•Evaluation of the establishment’s compliance with GMP
requirements
•Evaluation of the procedures and controls implemented
in the mfg
•Audit of the completeness and accuracy of the mfg and
testing information submitted with the application
•The collection of samples for the validation or
verification of the analytical methods included in the
application.
115
Types of Inspection
 Routine Inspection
 Concise Inspection
 Follow up Inspection
 Special Inspection
 Investigative Inspection
116
When Inspections are Required?
 New chemical entity
 Drugs of narrow therapeutic range
 Products previously associated with serious adverse
effects, complaints, recalls
 Applications from manufacturers who have
previously failed to comply with GMP or official
quality specifications.
 Products that are difficult to manufacture or test, or
that are of doubtful stability
 New applicants or manufacturers
117
WHO’s guidance on
interchangeability of medicines
Guidance
on selection of comparator products for
equivalence assessment of interchangeable generic
products

New draft: BCS classification to limit in vivo tests

In vitro test methodology for BCS class I drugs
118
Why is bioequivalence needed ?
•Pharmaceutical equivalence does not necessarily mean
therapeutic equivalence
• Multisource drug products should conform to the same
standards of quality, safety and efficacy required for the
reference product and must be interchangeable.
• Differences in excipients or manufacturing process
may lead to differences in product performance. Also, in
vitro dissolution does not necessarily reflect in vivo
bioavailability.
119
What are the ways of demonstrating
therapeutic equivalence ?
• Comparative BA ( BE ) studies
• Comparative pharmacodynamic studies in
humans
• Comparative clinical trials
• In vitro dissolution tests
120
When BE Studies are not needed for
Multisource product ?
A) An aqueous solution for parenteral use
B) A solution for oral use
C) A medicinal gas
D) A powder for reconstitution as a solution for oral or parenteral
use
E) An otic or ophthalmic solution
F) A topical aqueous solution
G) An inhalation product or nasal spray as an aqueous solution
For e, f and g, formulation of multisource product must be similar to
reference product.
Also, bioequivalence studies may be waived for compositionally
similar strengths when one strength in a range has been studied.
121
Design of comparative BA studies
• Studies should be carried out in accordance with
provisions of guidelines on Good Clinical Practice,
Good Manufacturing Practice, Good Laboratory
Practice
• Most common design is single-dose, randomized,
two-way crossover study (non-replicated)
• Other designs possible, e.g. parallel design for drugs
with long half-lives, steady-state studies for some
non-linear drugs
122
Factors to consider in the design of a study
 Study formulation should be representative of formulation to be marketed
• Subjects
- number
- health status
- age, weight, height
- ethnicity
- gender
- special characteristics e.g. poor metabolizers
- smoking
- inclusion/exclusion criteria specified in protocol
• Randomization
• Blinding
• Sampling protocol
• Washout period
• Administration of food and beverages during study
• Recording of adverse events
123
Bioequivalence standards (acceptance ranges)
• The 90% confidence interval of the relative mean AUC of the
test to reference product should be between 80-125%.
• The 90% confidence interval of the relative mean CMAX of the
test to reference product should be between 80-125%. Since
CMAX is recognized as being more variable than the AUC ratio,
a wider acceptance range may be justifiable.
• These standards must be met on log-transformed parameters
calculated from the measured data
• If the measured potency of the multisource formulation differs
by more than 5% from that of the reference product, the
parameters may be normalized for potency.
• TMAX may be important for some drugs
124
Critical parameters to look into when evaluating
dossiers with respect to BE studies
1. Is the reference product suitable?
2. Was the study design such that variability due to
factors other than the product was reduced? Other
design issues e.g. sample size, sampling protocol
3. Assay validation adequate?
4. Pharmacokinetic analysis appropriate?
5. Statistical analysis appropriate?
6. Acceptance criteria met?
125
Some statistical considerations
• A priority specification of methods
Statistical methods to be used must be specified beforehand in
the protocol
• Number of subjects
Minimum 12 subjects. Usually 18-24 subjects sufficient.
• Log-transformation
AUC and CMAX should be analyzed after log-transformation
Satisfies assumption of Analysis of Variance (ANOVA model is
additive rather than multiplicative)
• Outliers
Must be valid medical reason to drop outlier from analysis
Post hoc deletion of outlier values is generally discouraged
Parametric methods are recommended for the analysis of logtransformed BE measures
Non-parametric methods can be used when the log transformed data is
not normal
126
Pharmacodynamic studies
Not recommended : for oral product for systemic action due
to high within-subject variability
Used :
•If quantitative analysis of the drug and/or metabolite(s) in
plasma or urine can’t be made with sufficient accuracy and
sensitivity
•If measurements of drug concentration can’t be used as
surrogate endpoints for the demonstration of efficacy and
safety of the particular pharmaceutical product
127
WHO Model System for
Computer-assisted Drug Registration
(SIAMED)
Objective
To improve the efficiency of drug
regulatory authority (DRA) enabling them
to assure that marketing authorizations
are consistent with their national drug
policy.
128
What does the model
system do?
- Information on companies,
- Summary information on inspections carried out at company
premises
- Information on medicinal products for which an application has
been received or a marketing authorization is issued,
- Status of applications in the evaluation process.
- Decisions such rejection, issuance, cancellation, renewal, and
variation to marketing authorizations
- Variations to valid marketing authorizations, automatically keeping
history of all variations made.
129
PROVISIONS AND PREREQUISITES FOR A
CLINICAL TRIAL
•Justification for the trial
- Ethical principles : As per current version of Declaration of
Helsinki
- Supporting data for the investigational product:
Pre-clinical studies
Information about manufacturing procedures
compilation of information on safety and efficacy
based on previous Clinical data for subsequent trials
- Investigator and site(s) of investigation
- Regulatory requirements
130
THE PROTOCOL: Clinical trial should be carried out in
accordance with a written protocol agreed upon and signed by the
investigator and the sponsor
PROTECTION OF TRIAL SUBJECTS
Declaration of Helsinki: Recommendations guiding physicians in
biomedical research involving human subjects
It is the accepted basis for clinical trial ethics & must be fully
followed and respected by all parties.
Ethics committee
It ensure the protection of the rights and welfare of human subjects
participating in clinical trials, and to provide public reassurance,
by previewing trial protocols, etc.
131
Confidentiality
The investigator must establish secure safeguards of
confidentiality of research data as described in the
current revision of the International Ethical Guidelines
for Biomedical Research Involving Human Subjects.
132
RECOMMENDED GUIDELINES FOR ORGANIZATIONS
SUCH AS CONTRACT RESEARCH ORGANIZATIONS
(CROs) PERFORMING BE STUDIES ON BEHALF
OF SPONSORS
This document provide guidelines to organizations such as CROs
that are involved in the conduct of in vivo BE studies.
This document provides information on:
- organization and management;
- clinical phase of a study;
- bioanalytical phase of a study;
- pharmacokinetic and statistical analysis; and
-study report.
133
ROLE OF THE DRUG REGULATORY
AUTHORITY
-Provides the legal framework for clinical trials
-Have a mandate to review protocols and, where
necessary, to protect the safety of subjects, to require
protocol revisions and/or termination of trials.
-Carry out on-site inspections of the clinical trial site.
134
WHO GMP:
Investigational pharmaceutical products for
clinical trials in humans
The present guidelines supplement both the WHO guide on GMP and
the guidelines on GCP.
why application of the principles of GMP is necessary???
• To assure consistency between and within batches of the
investigational product & thus assure the reliability of clinical trials.
• To assure consistency between the investigational product & the
future commercial product and therefore the relevance of the clinical
trial to the efficacy and safety of the marketed product.
• To protect subjects of clinical trials from poor-quality products
resulting from manufacturing errors, or from starting materials and
components of inadequate quality.
• To document all changes in the manufacturing process.
135
WHO’s global guidelines –
DISTRIBUTION
WHO Certification Scheme for Products Moving in
International Commerce

SMACS new scheme for pharmaceutical starting
materials: - model certificate, when inspected by national authority

-
WHO model for self-assessment for manufacture of pharmaceutical
starting materials
 Good Distribution and Trading Practices for pharmaceutical starting
materials (GTDP)

Good Distribution Practices (GDP) (for products in prep.)

Good Storage Practices (GSP)
136
Guidelines on the implementation of the WHO
certification scheme on the QUALITY OF
PHARMACEUTICAL PRODUCTS moving in
international commerce
The Scheme is an administrative instrument that requires each
participating Member State, to attest to the competent authority of
another participating Member State that:
 - A specific product is authorized or, if it is not authorized,
the reason why that authorization has not been accorded;
 - The plant is subject to inspections at suitable intervals to
establish that the manufacturer conforms to GMP;
 - All submitted product information, including labelling, is
currently authorized in the certifying country.
137
Eligibility for participation
Any Member State intending to participate in the
Scheme may do so by notifying the Director-General
of the WHO, in writing, of:

Its willingness to participate in the Scheme;

Any significant reservations it intends to observe
relating to this participation; and

The name and address of its national drug
regulatory authority or other competent authority.
138
-A Member State may opt to participate solely to control the
import of pharmaceutical products and active substances. This
intention should be stated explicitly in its notification to the WHO
-A Member State intending to use the Scheme to support the
export of pharmaceutical products should first satisfy itself that it
possesses:
• An effective national licensing system
• GMP requirements, as recommended by WHO
• Effective controls to monitor the quality of pharmaceutical
products
• A national pharmaceuticals inspectorate,
• Administrative capacity to issue the required certificates,
139
Requesting a certificate
Three documents can be requested within the scope
of the scheme:
a) Certificate of a Pharmaceutical Product (Product
certificate)
b) Statement of Licensing Status of Pharmaceutical
Product (s)
c) Batch Certificate of a Pharmaceutical Product.
140
WHO pharmaceutical starting materials
certification scheme (SMACS): guidelines
on implementation
141
Objectives
The Scheme is an administrative instrument that can be
used by:
1) A Member State to attest that:
— A specific starting material is authorized to be placed on
the market and
—The manufacturing site is subject to inspections at suitable
intervals to establish that the manufacturer conforms to GMP
as recommended by WHO.
2)Manufacturer to attest compliance with a quality
assurance system
142
Contents of the GTDP( starting material)
& GDP( Pharmaceutical products)
- Quality management
-Organization and
personnel
- Complaints
- Recalls
- Returned goods
-Premises
- Handling of nonconforming materials
- Warehousing and
storage
- Dispatch and transport
- Equipment
- Contract activities
- Documentation
- Repackaging and relabelling
143
WHO GMP Guidelines for
pharmaceutical products
144
GMP for pharmaceutical products: MAIN
PRINCIPLES
The following points are covered in the recent one.
1. Quality Assurance
- Is achieved by following GMP, GCP and GLP.
2. GMP
3. Sanitation and hygiene-A high level of
sanitation and hygiene should be practised
4. Qualification AND validation
5. Complaints
6. Product recalls
145
7. Contract production and analysis
-Contract giver
--contract acceptor- cannot pass it on to a third party without prior
approval of a contract giver.
8. Self inspection and quality audits
-Quality audit- is to supplement self inspection, is the assessment of
a part of or complete quality system with the specific purpose of
improving it.
9. Personnel
10. Training
11. Personal hygiene
12. Premises
Ancillary, storage, weighing, production, quality control areas.
13.Equipment- be suitable for its intended use; facilitate thorough
cleaning; minimize the risk of contamination of products and
containers during production; and facilitate efficient and, if
applicable, validated and reliable operation.
146
14. Materials
15. Documentation
16. Good practices in production
-Prevention of cross contamination
-Processing operation
-Packaging operation
17. Good practices in Quality control
-Control of starting materials, intermediates, bulk and finished products.
-Test requirements- the materials have been tested for conformity with
specifications for identity, strength, purity and other quality parameters.
-Batch record review-Production and quality control records
--Stability studies-Stability should be determined prior to marketing and
following
any significant changes in processes, equipment, packaging materials .
147
WHO GMP: STARTING MATERIALS
ACTIVE PHARMACEUTICAL INGREDIENTS (bulk
drug substances)
1. Explanation- the guideline gives procedures and practices that
manufacturer should employ to get products having quality and
purity appropriate for their use in pharmaceutical products.
2. General consideration-these guideline are for human as well as
veterinary use.
3. Personnel4. Equipment5. Premises –for cytostatic substances antibiotics etc , there should
be separate areas with separate AHU.
6. Documentation-includes master formulae records, batch formulae
records and SOP’s . Outdated master formulae records should be
withdrawn but should be retained for reference.
Batch records electronically stored should be protected by back up
transfer or magnetic tape, microfilm , paper print outs etc.
148
6. Retention of records and reference samples- of the API, and where
necessary of intermediate products, should be retained for at least 1
year beyond the expiry date of the finished product or for a specified
period if there is no expiry date.
7. Production- -Processing procedures
-Starting materials- Some may not be tested for compliance because of
the hazards involved (e.g., phosphorus pentachloride and dimethyl
sulfate). This is acceptable when a batch certificate of analysis is
available from the vendor and when there is a reason based on safety
or other valid considerations.
-Intermediate products
-Packaging
8. Quality control
9. Stability studies- expiry date do not usually need to be set for active
pharmaceutical ingredient, if the stability testing does not indicate a
reasonable shelf life, then the product can be labeled with an
appropriate arbitrary expiry date and should be retested on or before
that date.
10. Self inspection and quality audits
11. Storage
12. Complaints defects and rejected samples.
149
WHO good manufacturing practices: starting
materials
Pharmaceutical EXCIPIENTS
1. General considerations –
• An excipient manufacturer should be able to identify
critical or key points
in the process where selective intermediate sampling and
testing is necessary in order to monitor process
performance.
2. Self-inspection
it is a review of the following areas:
• Non-conformance
• Complaint files.
• Change control documentation.
150
3. Quality Audits
Master formula and batch production records.
• Specifications for the presence of unreacted intermediates and solvent
residues in the finished excipient.
• Storage areas for rejected products.
• adequacy of measures taken to preclude contamination of materials in
the process.
4. Equipment -Use of equipment Equipment that contains tarry or gummy residues that cannot be
removed easily should be dedicated for use with these products only.
-Cleaning programme
- Detailed cleaning procedure
- Sampling plan
- Analytical methods/cleaning limits
5. Materials
-Starting materials –labile products
-- Rejected and recovered materials
- Returned excipients
151
6. Documentation
Specifications ,Batch production records , Other documents
7. Good practices in production and quality control -Change
control and process validation ,
-Good practices in production
-Prevention of cross-contamination
-Control of microbial contamination
-Water systems/water quality
-Packaging operations
-Delivery
8.Good practices in quality control
-Control of starting materials -certificate of analysis from the
supplier
-In-process testing
-Quality records and retention samples
Reserve samples should be retained for 1 yr after the expiry or reevaluation date, or for 1yr after distribution is complete.
.-Stability studies
152
WHO GMP- HERBAL medicinal products
1.Glossary
2. General3. Premises•Medicinal plant materials should be stored in
separate areas.
•The storage of plants, extracts, tinctures and
other preparations may require special
conditions of humidity and temperature or
protection from light.
153
4. Production area- to avoid cross-contamination
whenever dust is generated, special precautions should be
taken during the sampling, weighing, mixing and
processing of medicinal plants.
5. Specifications for starting materials.The botanical name, with reference to the authors.
• Details of the source of the plant
• Whether the whole plant or only a part is used.
• When dried plant is purchased, the drying system.
• A description of the plant material based on visual
and/or microscopical inspection
. Assay
•Any treatment used to reduce fungal/microbial
contamination or other infestation should be documented.
154
6. Qualitative and quantitative requirements
Medicinal plant material: (a) the quantity of plant material must be
stated; or (b) the quantity of plant material may be given as a
range, corresponding to a defined quantity of constituents of
known therapeutic activity.
The composition of any solvent or solvent mixture used and the
physical state of the extract must be indicated
7. Specifications for the finished product
If the preparation contains several plant materials and a
quantitative determination of each active ingredient is not feasible,
the combined content of several active ingredients may be
determined.
8. Processing instructions- The processing instructions should list
the different operations to be performed on the plant material.
9. Quality control -Reference samples of plant materials must be
available for use in comparative tests.
155
10. Sampling
11. Stability tests –it must be shown that, substances present are
stable and that their content as a proportion of the whole remains
constant.
If it is not feasible to determine the stability of each
active ingredient, the stability of the product should be
determined
156
WHO GMP for STERILE pharmaceuticals products
General considerationsManufacturing operations are divided here
into 2 categories:
1. Terminally sterilized
2. Aseptically sterilized at some or all stages.
2.Quality control -The sterility of the finished product is
ensured by validation of the sterilization cycle in the
case of terminally sterilized products, and by “mediafills” runs for aseptically processed products.
Pharmacopoeial methods must be used for the validation
and performance of the sterility test.
3.Sanitation –because of limited effectiveness of ultraviolet
light it should not be used as a substitute for chemical
disinfection.
157
4.Manufacture of sterile preparations –
Limits for microbiological contamination
Grade
A
B
C
D
Air sample
Settle plates
(CFU/m3) (diameter 90mm)
(CFU/4 hours)
<3
<3
10
5
100
50
200
100
Contact plates Glove print
(diameter 55mm) (5 fingers)
(CFU/plate)
(CFU/glove)
<3
<3
5
5
25
—
50
—
5.Terminally sterilized products-The filling of products for terminal
sterilization should generally be done in at least a grade C
environment.
158
6.SterilizationThe sterilization is carried out by
Dry heat
Moist heat
radiation
Filtration
By gases and fumigants
7.Aseptic processing and sterilization by filtration
The objective is to maintain the sterility of a product that is
assembled from components, each of which has been
sterilized by one of the above methods.
8.Personnel –
9.Premises -Grade B areas should be designed in such a way
that all operations can be observed from outside.
159
10. Equipment –
A conveyor belt should not pass through a partition
between a
grade A or B clean area and a processing area of lower air
cleanliness, unless the belt itself is continuously
sterilized .
Equipment that has to be taken apart for maintenance
should be resterilized after complete reassembly,
wherever possible.
11.Finishing of sterile products- Containers should be closed
by appropriately validated methods. Samples should
be checked for integrity according to appropriate
procedures.
160
WHO GMP for RADIOPHARMACEUTICAL
products
1. Scope :
• The preparation of radiopharmaceuticals in hospital radiopharmacies.
• The preparation of radiopharmaceuticals in centralized
radiopharmacies.
• The production of radiopharmaceuticals in nuclear centers and
institutes or by industrial manufacturers.
• The preparation and production of radiopharmaceuticals in positron
emission tomography (PET) centers.
2.Principles-Because of their short half-lives, many radiopharmaceuticals
are released and administered to patients shortly after their
production, so that quality control may sometimes be retrospective.
Therefore a strict adherence to GMP is mandatory.
3. Personnel-person who has academic achievement together with a practical
expertise and experience in radiopharmacy and radiation hygiene
161
2.can be relied on to observe the appropriate codes of practice and
are not subject to any disease.
3. minimum number of personnel required should be present in
clean and aseptic areas when work is in progress.
4.personnel should be trained in GMP, the safe handling of
radioactive materials and radiation safety procedures.
5. Training records
4. Premises and equipment-
1.Specific disposal systems should be mandatory for radioactive
effluents.
2. Sinks should be excluded from aseptic areas. Any sink installed in
other clean areas should be of suitable material and be regularly
sanitized.
3. Separate air-handling units should be used for radioactive and
non-radioactive areas.
4.Proper HVAC
162
5.Production1.SOPs must be available for all operating procedures.
2. Specifications for starting materials.
3. Great care should be taken in cleaning, sterilizing and operating
freeze-drying equipment used for the preparation of kits.
4.For the measurement of very short half-lives, national central
laboratories should be contacted to calibrate the apparatus. Where
this is not possible, alternative approaches, such as documented
procedures, may be used.
5.If an inert gas such as nitrogen is used to fill vials, it must be
filtered to remove possible microbial contamination.
6. dispensing, packaging and transportation of
radiopharmaceuticals should comply with the relevant national
regulations and international guidelines.
6. Labelling-All products should be clearly identified by labels, which must
remain permanently attached to the containers under all storage
conditions.
163
-An area of the container should be left uncovered to allow
inspection of the contents.
-Information on batch coding must be provided to the national
and/or regional authorities.
7. Production and distribution records-Separate records for the receipt, storage, use and disposal of
radioactive materials
-Distribution records should be kept.
-The return of radioactive products should be carried out in
accordance with international and national transport
regulations.
8. Quality assurance and quality control-Quality assurance and/or quality control have the principal
responsibilities same as that for any other pharmaceutical
product.
164
WHO GMP for BIOLOGICAL products:
1. Scope:
Manufacturing procedures within the scope of these guidelines
include:
— growth of strains of microorganisms and eukaryotic cells,
— extraction of substances from biological tissues, including
human, animal and plant tissues (allergens)
— recombinant DNA (rDNA) techniques,
— hybridoma techniques,
— propagation of microorganisms in embryos or animals.
2. Principlesbiological products are manufactured by methods involving
biological processes and materials, such as cultivation of cells or
extraction of material from living organisms. These processes
display inherent variability. For this reason, in the manufacture of
biological products full adherence to GMP is necessary.
165
3. Personnel-The staff engaged in the manufacturing process should be separate
from the staff responsible for animal care.
-To ensure the manufacture of high-quality products, personnel should
be trained in GMP and GLP in appropriate fields such as bacteriology,
virology, biometry, chemistry, medicine, immunology and veterinary
medicine.
-All personnel engaged in production, maintenance, testing and animal
care (and inspectors) should be vaccinated with appropriate vaccines
and, where appropriate, be submitted to regular testing for evidence of
active tuberculosis.
4. Premises and equipment -Products such as killed vaccines, including those made by rDNA
techniques, toxoids and bacterial extracts may after inactivation be
dispensed into containers on the same premises as other sterile
biological products, providing that adequate decontamination
measures are taken after filling, including, if appropriate, sterilization
and washing.
166
-Spore-forming organisms shall be handled in facilities dedicated to this
group of products until the inactivation process is accomplished.
-Dedicated facilities and equipment shall be used for the manufacture of
medicinal products derived from human blood or plasma.
5. Animal quarters and care -Animals shall be accommodated in separate buildings with self-contained
ventilation systems.
-The buildings' design and construction materials shall permit
maintenance in a clean and sanitary condition free from insects and
vermin.
-The health status of animals from which starting materials are derived
and of those used for quality control and safety testing should be
monitored and recorded.
-Provision shall also be made for animal inoculation rooms, which shall be
separate from the postmortem rooms.
-There shall be facilities for the disinfection of cages, if possible by steam,
and an incinerator for disposing of waste and of dead animals
167
6. Production –
-Standard operating procedures
-Specifications for starting materials
- Media and cultures shall be added to fermenters and other vessels
under carefully controlled conditions to avoid contamination. Care
shall be taken to ensure that vessels are correctly connected when
cultures are added.
-If possible, media should be sterilized in situ. In-line sterilizing filters
for routine addition of gases, media, acids, alkalis, defoaming agents,
etc. to fermenters should be used
-consideration should be given to the validation of sterilization
methods.
7. Labelling-All products shall be clearly identified by labels.
-The information given on the label on the container and the label on
the package shall be approved.
-The leaflet in the package should provide instructions for the use of
the product, and mention any contraindications or potential adverse
reactions.
168
-The label on the package should show at least the nature and amount of any
preservative or additive in the product.
8. Lot processing records (protocols) and distribution records –
Processing records of regular production lots must provide a
complete account of the manufacturing history of each lot of a
biological preparation.
9. Quality assurance and quality control-In-process controls very important here
-Tests that are crucial for quality control but that cannot be carried
out on the finished product shall be performed at an appropriate
stage of production.
-Special consideration needs to be given to the quality control
requirements arising from production of biological products by
continuous culture.
169
WHO Guidelines to GOOD STORAGE PRACTICES for
pharmaceuticals
1.Introduction -involved in the storage, transportation
and distribution of pharmaceuticals.
-It is closely linked to other existing guides recommended by the
WHO Expert Committee on Specifications for Pharmaceutical
Preparations, such as:
•
Good trade and distribution practice (GTDP) of pharmaceutical
starting materials.
• The stability testing of pharmaceutical products
• The cold chain, especially for vaccines and biologicals;
• The International Pharmacopoeia
This guidance has been prepared in close collaboration with the
International pharmaceutical Federation (FIP).
170
2. Personnel•All personnel should receive proper training in relation to good
storage practice, regulations, procedures and safety .
• Personnel employed in storage areas should wear suitable protective
or working garments appropriate for the activities they perform.
3. Premises and facilities –
-Precautions must be taken to prevent unauthorized persons from
entering storage areas.
-sufficient capacity
-Storage areas should be designed or adapted to ensure good
storage conditions.
-clean, and free from accumulated waste and vermin.
-Receiving and dispatch bays should protect materials and products
from the weather .
-The materials or products, and areas concerned should be appropriately
identified.
- The “first expired/first out” (FEFO) principle should be followed.
171
4. Storage requirements
Storage conditions should be in compliance with the labelling.
Monitoring of storage conditions
-Recorded temperature monitoring data should be available for
review.
-All monitoring records should be kept for at least the shelf-life of the
stored material or product plus 1 year.
5. Storage requirementsDocumentation: written instructions and records
Labelling and containers
Receipt of incoming materials and pharmaceutical products
Stock rotation and control-Periodic stock reconciliation should be
performed by comparing the actual and recorded stocks.
Control of obsolete and outdated materials and pharmaceutical
Products
172
6.Returned goods• including recalled goods, should be handled in accordance with
approved procedures and records should be maintained.
•All returned goods should be placed in quarantine
Any stock reissued should be so identified and recorded in stock
records.
•Pharmaceuticals returned from patients to the pharmacy should not
be taken back as stock, but should be destroyed.
7. Dispatch and transport•Materials and pharmaceutical products should be transported in
such a way that their integrity is maintained.
•The dispatch and transport of materials and pharmaceutical products
should be carried out only after receipt of a delivery order.
•All records should be readily accessible and available on request.
8. Product recall
173
MISCELLANEOUS
WHO action to address Substandard and Counterfeit
medicines
WHO provides support to countries to strengthen
-pharmaceutical legislation
-Good Manufacturing Practices (GMP)
- national drug regulatory capacity and performance
- to promote information exchange among drug regulatory
authorities –
-to strengthen drug procurement.
174
ECBS – Expert Committee on Biological Standardization
The WHO Expert Committee on Biological Standardization
is commissioned by WHO
Its function is to- establish detailed recommendations and
guidelines for the manufacturing, licensing, and control of
blood products, cell regulators, vaccines and related in vitro
diagnostic tests.
The Expert Committee on Biological Standardization meets on an
annual basis since 1947.
The Expert Committee directly reports to the Executive
Board, which is the executive arm of the World Health
Assembly.
175
INTERNATIONAL PHARMACOPOEIA
The desire for the unification of terminology and of the strengths and
composition of drugs led on to attempts to produce an international
pharmacopoeia.
The work on The International Pharmacopoeia is carried out in
collaboration with members of the WHO Expert Advisory Panel on
the International Pharmacopoeia and Pharmaceutical Preparations as
well as specialists from industry and other institutions.
The information published in it is collated via a consultative procedure
and may thus be regarded as being based on international experience.
The current edition completes the list of monographs for active
pharmaceutical substances. It also includes a number of important
general texts, e.g. on the dissolution test, drug nomenclature, general
specifications for dosage forms, and many more.
176
•The needs of developing countries are taken into account
and simple, classical physicochemical techniques are
recommended that have been shown to be sound.
• Whenever possible, classical procedures are used in the
analytical methods so that the pharmacopoeia can be
applied without the need for expensive equipment.
•Priority is given to drugs that are widely used
throughout the world. High priority is accorded to drugs
that are important to WHO health programmes, and
which may not appear in any other pharmacopoeias, e.g.
new antimalarial drugs.
•Unlike other pharmacopoeias, the International
Pharmacopoeia has no legal status.
•WHO Member States can adopt it and incorporate it into
national legislation, either in part or in whole.
177
Essential Drugs and Medicines Policy
WHO gives a list of essential drugs•Essential medicines are those that satisfy the priority
health care needs of the population.
They are selected in regard to public health relevance,
evidence on efficacy and safety, and comparative costeffectiveness.
•Essential medicines are intended to be available within
the context of functioning health systems at all times in
adequate amounts, in the appropriate dosage forms,
with assured quality and adequate information, and at a
price the individual and the community can afford.
178
References
 www.who.int/medicines
179
ICH
TRIPARTITE
GUIDELINES
CONTENTS
Introduction
What is ICH?
Topics of ICH
Quality Topics
Q1A (R2): Stability testing of New Drug Substances
and Products.
6) Q1B: Photostability testing
7) Q1C: Stability testing of new dosage forms
8) Q1D: Bracketing and Matrixing designs
9) Q1E: Evaluation of Stability data
10) Q1F: Stability data package for registration in
climatic zones III and IV.
11) References
12) Study Questions
1)
2)
3)
4)
5)
181
 Patient taking a pharmaceutical product
expect the product to be safe and efficacious.
 Pharmaceutical regulatory agencies
worldwide demand that the product retains
its identity, quality, purity and potency for the
time the product is commercially available.
 They also requires stability data supporting
the proposed expiry date of the product.
 Various stability guidelines describe the type
of studies & type of data needed.
182
Purpose of stability testing:
 To provide evidence of how the quality of drug substances
or products varies with time under the influence of
environmental factors.
 To establish a re-test period for the drug substances or the
shelf-life for the drug products and recommended storage
conditions.
 To ensure that the drug products retain their full efficacy
until the end of their expiration date.
Most important Guidelines:





Food and Drug Administration (FDA)
International Conference on Harmonization (ICH)
European Union Guidelines (EU)
Japanese Guidelines (MHW)
World Health Organization (WHO) Guidelines.
183
 Prior to 1960s there were not many controls over
introduction of new drugs and also over the assurance
of the quality by the manufacturer over his established
drug products.
 Around 1970s the pharmaceutical industry started
getting global but the registration of medicines
remained a national responsibility.
 So the companies had to duplicate many time
consuming and expensive test procedures, in order to
market new products, internationally. All this resulted
in unnecessary expenses and long delays in
introducing new drugs.
 So a necessity to harmonize, the testing procedures
and regulatory requirements of different countries was
felt and the result is the birth of ICH in April 1990.
184
ICH - The International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals
for Human Use.
Aim: It is a unique project that brings
together the regulatory authorities of
Europe, Japan and the United States and
experts from the pharmaceutical industry
in the three regions to discuss scientific
and technical aspects of product
registration.
OBJECTIVES
• More economical use of human, animal & material resources.
• Elimination of unnecessary delay in the global development
& availability of new medicines.
• Maintaining safeguards on Quality, Safety & Efficacy, and
regulatory obligations to protect the public health.
185
TOPICS OF ICH
Quality (Q): Topics related to
Manufacturing QA.
Safety (S): Topics related to nonclinical pharmacology &
toxicology studies.
Efficacy (E): Topics related to Clinical
studies in humans.
Multidisciplinary (M): Topics affecting
more than one
discipline.
Our concern is only with quality topics.
186
QUALITY TOPICS
Consists of six subtopics:Q1: Stability testing
Q2: Analytical methods validation
Q3: Impurity testing
Q4: Pharmacopoeias
Q5: Quality of Biotechnological products
Q6: Specifications for new drug
substances & products.
Our concern is only Q1.
187
SPECIFIC GUIDELINES UNDER Q1
Q1A (R2): Stability testing of new drug substances and
products.
Q1B:
Photostability testing.
Q1C:
Stability testing of new dosage forms.
Q1D:
Bracketing & Matrixing designs for stability
testing of new drugs substances and products.
Q1E:
Evaluation of Stability data.
Q1F:
Stability Data Package for Registration
Applications in Climatic Zones III and IV
188
Q1A (R2):
STABILITY TESTING OF NEW
DRUG SUBSTANCES AND
PRODUCTS
1. INTRODUCTION
1.1 Objectives of the Guideline.
1.2 Scope of the Guideline.
1.3 General Principles.
189
2. GUIDELINES
2.1 DRUG SUBSTANCES
2.1.1 General
2.1.2 Stress Testing
2.1.3 Selection of Batches
2.1.4 Container Closure System
2.1.5 Specification
2.1.6 Testing Frequency
2.1.7 Storage Conditions
2.1.8 Stability Commitment
2.1.9 Evaluation
2.1.10 Statements/Labeling
190
Q1B:
PHOTOSTABILITY TESTING
OF NEW DRUG
SUBSTANCES AND DRUG
PRODUCTS
191
CONTENTS
1. GENERAL
A. PREAMBLE
B. LIGHT SOURCES
C. PROCEDURE (DECISION FLOW CHART)
2. DRUG SUBSTANCES
A. PRESENTATION OF SAMPLES
B. ANALYSIS OF SAMPLES
C. JUDGEMENT OF RESULTS
3. DRUG PRODUCTS
A. PRESENTATION OF SAMPLES
B. ANALYSIS OF SAMPLES
C. JUDGEMENT OF RESULTS
4. ANNEX
A. QUININE CHEMICAL ACTINOMETRY
192
1. GENERAL
The light testing should be an integral part of the stress
testing.
A. PREAMBLE
Normally, photo-stability testing is carried out on a
single batch of material selected as described under
Selection of Batches in the Parent Guideline.
Following studies are covered such as:
1) Tests on the drug substance
2) Tests on the exposed drug product outside of the
immediate pack; and if necessary;
3) Tests on the drug product in the immediate pack; and if
necessary
4) Tests on the drug product in the marketing pack.
193
B. Light sources. (Defined in ISO 10977 (1993))
An appropriate control of temperature should be maintained to
minimize the effect of localized temperature changes.
Option 1:
Any light source that is designed to produce an output similar to the
D65/ID65 emission standard such as an artificial daylight
fluorescence lamp combining visible and ultraviolet (UV) outputs,
xenon or metal halide lamp.
D65 is the internationally recognized standard for outdoor daylight.
ID65 is the equivalent indoor indirect daylight standard.
Option 2:
Same sample should be exposed to both the cool white fluorescent
and near ultraviolet lamp (having a spectral distribution from 320 to
400 nm with a maximum energy emission between 350 & 370 nm)
194
C. PROCEDURE
 An overall illumination of not less than 1.2 million
lux hours and an integrated near ultraviolet energy
of not less than 200 watt hours/square meter to
allow direct comparisons to be made between the
drug substance and drug product.
 Samples may be exposed side-by-side with a
validated chemical actinometric system to ensure
that the specified light exposure is obtained.
 If protected samples (e.g., wrapped in aluminum
foil) are used as dark controls to evaluate the
contribution of thermally induced change to the
total observed change, these should be placed
alongside the authentic sample.
195
START
FORMULATION
CHANGE?
YES
DIRECTLY EXPOSED
ACCEPTABLE
CHANGE?
NO
DECISION FLOW CHART
FOR PHOTOSTABILITY
TESTING OF DRUG
PRODUCTS
YES
TEST END
NO
IMMEDIATE
PACK
CHANGE?
YES
IMMEDIATE PACK
ACCEPTABLE
CHANGE?
NO
YES
TEST END
NO
MARKETING
PACK
CHANGE?
YES
MARKETING PACK
ACCEPTABLE
CHANGE?
NO
REDESIGN PACKAGE
OR REFORMULATION
YES
TEST END
196
2. DRUG SUBSTANCES
Photo-stability testing should consist of two parts:
1. Forced degradation testing:
To evaluate the overall photosensitivity of the
material for method development purposes and/or
degradation pathway elucidation.
2. Confirmatory testing:
To provide information necessary for handling,
packaging and labeling.
A. Presentation of samples
B. Analysis of samples
C. Judgement of Results
3. DRUG PRODUCTS
197
4. ANNEX
A. Quinine Chemical Actinometry
Each actinometric system should be calibrated for the light source
used, by 2% W/V aqueous solution of quinine
monohydrochloride dihydrate.
Option 1: Use 20 ml colourless ampoules. (seal hermetically).
Option 2: Use 1 cm quartz cell.
 For both the options, prepare sample and control wrap in
aluminum foil to protect completely from light, and measure their
absorbance At and Ao respectively at 400 nm using a 1 cm path
length. Measure the change in absorbance.
 The length of exposure should be sufficient to ensure a change in
absorbance of at least 0.9.
198
Q1C:
STABILITY TESTING OF
NEW DOSAGE FORMS
199
1. GENERAL
 This document is an annex to the ICH parent stability
guideline and addresses the recommendations on
what should be submitted regarding stability of new
dosage forms.
2. NEW DOSAGE FORMS
 Stability protocols for new dosage forms should follow
the guidance in the parent stability guideline.
However, a reduced stability database at submission
time (e.g., 6 months accelerated and 6 months long
term data from ongoing studies) may be acceptable in
certain justified cases.
STABILITY STUDY PROTOCOLS: Same as Q1A(R2)
200
Q1D:
BRACKETING AND
MATRIXING DESIGNS FOR
STABILITY TESTING OF
NEW DRUG SUBSTANCES
AND PRODUCTS
201
CONTENTS
1. INTRODUCTION
1.1 OBJECTIVES OF THE GUIDELINE
1.2 BACKGROUND
1.3 SCOPE OF THE GUIDELINE
2. GUIDELINES
2.1 GENERAL
2.2 APPLICABILITY OF REDUCED DESIGNS
2.3 BRACKETING
2.4 MATRIXING
2.5 DATA EVALUATION
202
2. GUIDELINES
2.1 General
STUDY
DESIGN
FULL STUDY
DESIGN
REDUCED
STUDY
DESIGN
BRACKETING
MATRIXING
203
2.2 Applicability of reduced designs
Reduced designs can be applied to the formal stability study
of most types of drug products.
For the study of drug substances, Matrixing is of limited
utility and bracketing is generally not applicable.
Data variability and product stability, should be considered
when a matrixing design is applied.
2.3 Bracketing
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 an intermediate
levels is represented by the stability of the extremes tested.
2.3.1 Design Factors
Design factors are variables (e.g., strength, container size
and/or fill) to be evaluated in a study design for their effect
204
on product stability.
2.3.1.1 Strength
Bracketing can be applied to studies with multiple
strengths of identical or closely related formulations.
Examples include:
Capsules, tablets and oral solutions of different
strengths.
In cases, where different excipients are used among
strengths, bracketing generally should not be applied.
2.3.2.2 Container closure sizes and/or fills.
Bracketing can be applied to studies of the same
container closure system where either the container
size or fill varies while the other remains constant.
However, if a bracketing design is considered where
both container size and fill vary, it should not be
assumed that the largest and smallest containers
represent the extremes of all packaging configurations.
205
2.3.2 Design considerations and Potential risks
If, after starting the studies, one of the extremes is no longer
expected to be marketed, study design can be maintained to
support the bracketed intermediates.
A commitment should be provided to carry out stability
studies on the marketed extremes post-approval.
Before a bracketing design is applied, its effect on the retest
period or shelf life estimation should be assessed.
If the stability of the extremes is shown to be different, the
intermediates should be considered no more stable than the
least stable extreme (i.e., the shelf life for the intermediates
should not exceed that for the least stable extreme).
206
2.3.3 Design example:
207
2.4. Matrixing
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.
At a subsequent time point, another subset of
samples for all factor combinations would be
tested.
The design assumes that the stability of each
subset of samples tested represents the stability
of all samples at a given time point.
208
2.4.1 Design factors
(Same as in bracketing)
2.4.2 Design considerations
A matrixing design should be balanced as far as
possible so that each combination of factors is tested to
the same extent over the intended duration of the
study and through the last time point prior to
submission.
In a design where time points are matrixed, all selected
factor combinations should be tested at the initial and
final time points, while only certain fractions of the
designated combinations should be tested at each
intermediate time point.
209
2.4.3 Design examples:
“One-Half Reduction”
“One-Third Reduction”
210
2.4.4 Applicability and degree of reduction
Knowledge of data variability.
Expected stability of the product.
Availability of the supporting data.
Stability differences in the product within a factor or
among factors.
 Number of factors combinations in the study.




 In general, a matrixing design is applicable if the
supporting data indicate predictable product
stability.
 If the supportive data show large variability, a
matrixing design should not be applied.
2.4.5 Potential risk
2.5 Data Evaluation
211
Q1E:
EVALUATION OF
STABILITY DATA
212
1. INTRODUCTION
1.1 Objectives of the Guideline
This guideline is intended to provide recommendations on how
to use stability data generated in accordance with the principles
detailed in the ICH guideline “Q1A(R)” (here after referred as the
parent guideline) to propose a retest period/shelf life in a
registration application.
This guideline describes when and how extrapolation can be
considered when proposing a retest period for a drug substance
or a shelf life for a drug product that extends beyond the period
covered by “available data from the stability study under the
long-term storage condition” (hereafter referred to as long-term
data).
1.2 Background
The parent guideline states that regression analysis is an
important approach to analyzing quantitative stability data for
retest period or shelf life estimation and recommends that a
statistical test for batch poolability be performed using a level of
significance of 0.25.
213
1.3 Scope of the Guideline
This guideline addresses the evaluation of stability data that
should be submitted in registration applications for new
molecular entities and associated drug products.
2. GUIDELINES
2.1 General principles
2.2 Data presentation
Data for all attributes should be presented in an appropriate
format (e.g., tabular, graphical, narrative) and an evaluation
of such data should be included in the application.
2.3 Extrapolation
Extrapolation is the practice of using a known data set to
infer the information about a future data.
Extrapolation to extend the retest period or shelf life beyond
the period covered by long-term data can be proposed in the
application, particularly if no significant change is observed
at the accelerated condition.
214
2.4. Data evaluation for re-test period or shelf
life estimation for drug substances or
products Intended for Room Temperature
Storage
2.4.1 No significant change at accelerated condition
2.4.1.1
Long-term and accelerated data
Showing a little or no change over
Time and little or no variability
2.4.1.2
Long-term or accelerated
Data showing change over
Time and/or variability.
The drug substance or product will
Remain well within the acceptance
criteria for that attribute during the
proposed Re-test Period or shelf life.
Statistical analysis of long
term data can be useful
In establishing a retest
Period or shelf life.
A statistical analysis is normally
Considered un-necessary.
215
2.4.2 Significant change at accelerated condition
2.4.2.1
No significant change at intermediate
condition
2.4.2.2
Significant change at intermediate
condition
The extent of extrapolation would depend
on whether long-term data for the
attribute are amenable to statistical
analysis
Data not amenable to
Statistical analysis
The proposed re-test period
or shelf life can be upto 3
months beyond the period
covered by long-term data
The proposed re-test period or
Shelf life should not exceed
the Period covered by longterm data
Data amenable to
Statistical analysis
The proposed re-test period or shelf
life should not be more than 6
months beyond, the period covered
by long-term data.
216
2.5 Data evaluation for re-test period or shelf life
estimation for drug substances or products
intended for storage below room temperature.
2.5.1 Drug substances intended for storage in a
refrigerator
2.5.2 Drug substances intended for storage in a
freezer
2.5.3 Drug substances intended for storage
below -20°C
217
2.6. General statistical approaches
Regression analysis is considered as appropriate approach
for evaluation of stability data for a quantitative attribute
and establishing a retest period or shelf life.
The relationship between an attribute and time can be
represented by a linear or non-linear function on an
arithmetic or logarithmic scale.
An appropriate approach to retest period or shelf life
estimation is to analyze a quantitative attribute (e.g.,
assay, degradation products) by determining the earliest
time at which the 95 % confidence limit for the mean
intersects the proposed acceptance criterion.
Upper and lower confidence limit (95%) should be
calculated and compared to acceptance criterion.
218
Q1F:
STABILITY DATA PACKAGE
FOR REGISTRATION
APPLICATIONS IN
CLIMATIC ZONES III AND
IV
219
CONTENTS
1. INTRODUCTION
1.1 OBJECTIVES OF THE GUIDELINE
1.2 BACKGROUND
1.3 SCOPE OF THE GUIDELINE
2. GUIDELINES
2.1 CONTINUITY WITH THE PARENT GUIDELINE
2.2 STORAGE CONDITIONS
2.2.1 General Case
2.2.2 Aqueous-based drug products packaged in
semi-permeable containers.
2.2.3 Tests at elevated temperature and/or extremes
of humidity
2.3 ADDITIONAL CONSIDERATIONS
220
 A product’s shelf life should be established according to
climatic conditions in which the product is to be marketed.
 Climatic conditions in countries where the product is to be
marketed should be carefully considered during drug
development phase. So the world has been divided into four
climatic zones based on prevalent annual climatic conditions.
 Storage conditions recommended by manufacturers on the
basis of stability studies are meant to guarantee the
maintenance of quality, safety and efficacy throughout the
shelf-life of product.
 Temperature and humidity determine the storage conditions
and so they greatly affect the stability of drug product.
221
DEFINITION AND STORAGE / TEST
CONDITIONS FOR FOUR CLIMATIC ZONES
Climatic
zones
Definition
Storage / Test
conditions
Examples
I
Temperate
Climate
21°C ± 2°C and
Northern Europe,
45% RH ± 5% RH Canada
II
Mediterranean & 25°C ± 2°C and
Southern Europe
Subtropical
60% RH ± 5% RH Japan, US.
climate
III
Hot dry climate
30°C ± 2°C and
Egypt, Sudan
35% RH ± 5% RH
IV
Hot humid
climate
30°C ± 2°C and
Central Africa,
75% RH ± 5% RH South Pacific.
222
2. GUIDELINES
2.1 Continuity with the parent guideline
 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 substance or product in a
freezer
 Stability commitment
 Evaluation
 Statements/labeling
223
2.2 Storage conditions
2.2.1 General case
TYPE OF
STUDY
STORAGE CONDITION MINIMUM TIME PERIOD
FOR CLIMATIC ZONES COVERED BY DATA AT
III and IV
SUBMISSION
LONG TERM
30°C ± 2°C/ 65%
RH ± 5% RH
12 months
ACCELERATED
40°C ± 2°C/ 75%
RH ± 5% RH
6 months
No intermediate storage condition for stability studies is
recommended for Climatic Zones III and IV.
224
2.2.2 Aqueous based drug product packaged in
semi-permeable containers
TYPE OF
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/ not more than 25%
RH ± 5% RH
6 months
The ratio of water loss rates at a given temperature is calculated
by the general formula:
(100 - Reference %RH / 100 - Alternative %RH)
ALTERNATIVE
%RH
REFERENCE
%RH
RATIO OF WATER LOSS
RATES AT A GIVEN
TEMPERATURE
65% RH
35% RH
1.9
75% RH
25% RH
3.0
225
2.2.3 Tests at elevated temperatures and/or
extremes of humidity
 Special transportation and climatic conditions outside the
storage conditions recommended in this guideline should
be supported by the additional data.
 Stability testing at a high humidity condition. Eg.
25°C/80%RH, is recommended for solid dosage forms in
water-vapour permeable packaging e.g., tablets in
PVC/aluminium blisters, intended to be marketed in
territories with extremely high humidity conditions in
Zone IV.
2.3. Additional considerations.
 If it cannot be demonstrated that the drug substance or
drug product will remain within its acceptance criteria
when stored at 30°C ± 2°C/65 % RH ± 5 % RH for the
duration of the proposed retest period or shelf life, the
following options should be considered: (1) a reduced
retest period or shelf life, (2) a more protective container
closure system, or (3) additional cautionary statements in
226
the labeling.
REFERENCES:
 ICH HARMONISED TRIPARTITIE
GUIDELINES
www.ich.org
 USP 2000
 Encyclopedia of Pharmaceutical
Technology, Vol-19: 227-235
 Drug Stability: Principles and Practices,
3rd Edition, edited by Jens T. Carstensen
and C. T. Rhodes
227
50/50
228