“WHO TRS Requirements on Pharmaceuticals
Moving in International Commerce”
Dr. A. Ramkishan
Deputy Drugs Controller (India)-(Incharge)
Office of Deputy Drugs Controller (India), Zonal Office
Central Drugs Standard Control Organization (CDSCO), Ahmedabad
Ministry of Health & Family Welfare, Govt. of India
www.cdsco.nic.in
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Disclaimer
The views expressed in this presentation are my own,
and I have no financial interests to disclose.
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Outline of presentation
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Organization and Health Infrastructure in India
Evolution of Indian Drug Legislation
Introduction to Ministry of Health & Family Welfare
Vision, Mission, Strategies, Values of CDCSO
Introduction of SLAs and CLAAs
Principles of Good Laboratory Practice (GLP)
Introduction to Good Engineering Practice (GEP)
Principles of Good Manufacturing Practice (GMP)
Recent advances in WHO TRS 970, 2012
 WPU; WPS; WS Qualification; Inspection of WS
 Recent advances in WHO TRS 957- 2010 & 961-2011
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Organization and Health Infrastructure in India
 Based on the federal nature of constitution, areas of operation have been
divided into Central Government and State Government
 7th schedule of constitution describes 3 items namely: Union List, State
List and Concurrent list.
 Some items like Public health, Hospitals, Sanitization etc fall in the State
list.
 The items having wider ramification at the national level like Family
Welfare, Population Control, Medical Education, Prevention of Food
Adulteration, Quality Control in manufacturing of drugs etc have been
included in the Concurrent list.
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Evolution of Indian Drug Legislation
Preamble
To regulate manufacture, sale, distribution and import of drugs,
cosmetics, Biologicals, medical devices and other products.
Objective
The Objective of Drugs & Cosmetics Act is to ensure that public are
supplied with safety, efficacy and quality of drugs (Sec. 3b).
Basic Philosophy
The basic philosophy of Drugs & Cosmetics Act is that the manufacturer
is responsible for the quality of drugs manufactured by them and the
Government/Regulatory Agencies will monitor the quality of drugs by
periodic inspections of the manufacturing and sales premises for
confirmation to the provisions of Drugs & Cosmetics Act and monitoring
the quality of drugs moving in the market by carrying out post market
surveillance.
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Evolution of Indian Drug Legislation Conti…
Principle
The principle on which the Drugs & Cosmetics Act function is by a
system of licensing under which all the activities involved in
manufacture, sale and distribution of Drugs & Cosmetics are
controlled.
Drug Regulatory System in India
Drug is in concurrent list of Indian Constitution. It is governed by
both Centre and State Governments under the Drugs & Cosmetics
Act, 1940 and Rules 1945 thereunder.
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Indian Drug Regulatory System:
Government of India
Ministry of Health Ministry of Science
& Technology
& Family Welfare
DGHS
Central Drugs
Standard Control
Organization
(CDSCO)
Indian Council
of Medical
Research
(ICMR)
BARC
(Radioactive)
Council of
Scientific &
Industrial
Research
(CSIR)
Ministry of
Chemicals &
Petrochemicals
National
Pharmaceutical
Pricing Authority
(NPPA)
Department of
Chemical &
Petrochemicals
(DCP)
Ministry of
Commerce &
Industry
Patent
Office
Dept. of
Commerce &
Pharmexil
Ministry of
Environment &
Forest
GEAC[Genetic
Engineering
Approval
Committee]
Department of
Biotechnology
DGFT
r-DNA
Advisory
Committee
Controller
General of
Patent
Review
Committee
Genetic
Manipulation
Department of
Pharmaceuticals
Regulatory/Apex/Committee
Functions
CDSCO Central Drugs Standard Control
Organization (1948)
Laying down standards, Clearance of new drugs,
CLAA items, Banning Drugs, Clinical Trails etc.
ICMR
Indian Council of Medical
Research (1911)
Formulates, Coordinates and Promotes biomedical
research & Ethical Principles
GEAC
Genetic Engineering Approval
Committee (1989)
Manufacture, Use, Import of Hazards
Microorganisms/Genetically Engineered Organisms
or Cells
DBT
Department of Biotechnology
(1986)
It promote transgenic research, molecular biology of
human genetic disorders, brain research, and
commercialization of diagnostic kits and vaccines for
communicable diseases
AERB
Atomic Energy Review Board
(1983)
Promotes Radio therapy & Research, Safety review
for Gamma Irradiators (Devices)
BARC
Bhabha Atomic Research Centre
(1967)
Promotes Isotopes application in Medicine & also
monitoring usage of radioactive materials
DTAB
Drug Technical Advisory Board
(1950)
To advise Central & State Govt. on Technical
Matters arising out of the Drugs & Cosmetics
RCGM
Review Committee on Genetic No Objection Certificate for Clinical Trial & also rManipulation (1989)
DNA strains,
DCC
Drug Consultative
(since 1951)
Committee Advisory Committee to DTAB and Central & State
Govt. for uniform implementation of Various
provisions of the Act
Introduction to Ministry of Health & Family
Welfare (MOH&FW)
 MOH&FW comprises 04 departments each of which is headed by a
Secretary to the Govt. of India
 Department of Health & Family welfare
 Department of AYUSH
 Department of Health Research
 Department of AIDS Control
 CDSCO is a separate division comes under DGHS, headed by DCG(I)
 Public health is one of the major objectives of Govt. of India and to achieve
this it is important that drugs/vaccines are available to the public are
Quality, Safety, Purity and Efficacious.
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10
Industry size :
25.8 Bn USD
Exports :
13.2 Bn USD
Imports:
3.52 Billion USD
Industry is growing @ 20% p.a
Domestic Market 2011-2012: 12.6 Bn USD
4th Largest in world in terms of Volume & ranks 13th in terms of Value
Export of Biotech products & Biopharmaceuticals ~US $1.36 Bn
Export of Vaccines- US $507.9 million (US $ 42 Bn by year 2015)
Manufacturing Facilities 172 US FDA Approved
India Stood First Globally with 2759 DMF filling Out of 7886 DMFs
US Pharmacopoeia has office in Hyderabad, India
USFDA has country office in Delhi, Mumbai
9,000 manufacturing units in the country
600,000 Retail & Wholesale Shops in India
153 EDQM certified facilities; 6th largest supplier of HIV drugs after
Germany
Drugs from India are exported to more than 200 countries
Vaccines from India are exported to more than 151 countries
Geographical Location of CDSCO
CDSCO North Zone (Ghaziabad)
CDSCO West Zone (Mumbai)
HQ
J&K
Chandigarh
New Delhi
CDSCO South Zone (Chennai)
CDSCO East Zone (Kolkata) Ahmedabad
*New Zonal Offices
: 2
(Ahmedabad & Hyderabad)
*Sub- Zonal Office
:3
*Port Offices/Airports
: 11
*Central Laboratories
:6
CDSCO, HQ
Kolkata
.
• Hyderabad
Goa
Bengaluru
Chennai
35 SLAs= 29 States+ 6 UTs
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Functions of CDSCO
Approval of new drugs and clinical trials
Import Registration and Licensing
License approving of Blood Banks, LVPs, Vaccines, r-DNA
products & some Medical Devices (CLAA Scheme)
Amendment to D &C Act and Rules
Banning of drugs and cosmetics
Grant of Test License, Personal License, NOCs for Export
Testing of New Drugs
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Functions of State Licensing Authorities
Licensing of Manufacturing Site for Drugs including API and
Finished Formulation
Licensing of Establishment for sale or distribution of Drugs
Approval of Drug Testing Laboratories
Monitoring of Quality of Drugs and Cosmetics marketed in the
country
Investigation and prosecution in respect of contravention of
legal provision
Recall of sub-standard drugs
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Principles of GLP and Regulatory requirements
Objectives of GLP
• GLP makes sure that the data submitted are a true
reflection of the results that are obtained during the
study.
• GLP also makes sure that data is traceable.
• Promotes international acceptance of tests.
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What is GLP?
 Good Laboratory Practice (GLP) deals with the organization, process and conditions
under which laboratory studies are planned, performed, monitored, recorded, reported &
archived. GLP practices are intended to promote the quality and validity of test data (part
58 CFR 21). OR
 GLP is a quality system concerned with the organizational process and the conditions
under which non clinical health & environmental safety studies are planned, performed,
monitored, recorded, archived & reported. (Ref. Jurg P. Seiler-Switzerland, GLP, 2nd
edition by Springer publication, 2005, Page 61).
 Schedule L-I regulations and guidelines have a significant impact on the daily operation of
an analytical laboratory.
 GLP is a regulation. It is not only good analytical practice. Good analytical practice is
important, but it is not enough. For example, the laboratory must have a specific
organizational structure and procedures to perform and document laboratory work. The
objective is not only quality of data but also traceability and integrity of data. But the
biggest difference between GLP and Non-GLP work is the type and amount of
documentation.
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Pharmaceutical product
Submitted to regulatory authority
Verification
Repetition of experiment
activities
(Direct confirmation)
or
Reconstruction of all
activities
(Indirect confirmation)
Judgment taken
Accept / Reject
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Part 1
Management and
infrastructure
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•
•
•
•
•
•
•
•
Part 2
Materials, equipment,
instruments and other
devices
• Reagents
Organization and
management
• Reference
substances and
Quality management
reference materials
system
• Calibration, verifi
Control of documentation
cation of performance
Records
and
Data-processing equipment
• qualification of
Personnel
equipment,
Premises
instruments and other
Equipment, instruments and
devices
other devices
• Traceability
Contracts
Part 3
Working procedures
Part 4
Safety
• Incoming samples • General
• Analytical
rules
worksheet
• Validation of
analytical
procedures
• Testing
• Evaluation of test
results
• Certificate of
analysis
• Retained samples
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Storage and Archival
General Requirements
Raw Data
Premises
Personal
Protocols and
Specifications Archive
Standard Operating
Procedures
Equipments
Chemicals and Reagents
GLP
Good House Keeping
and Safety
Management Review
Maintenance, Calibration,
and
Validation of Equipments
Internal Quality
System Audits
Quality System
Reference Materials
Microbiological Cultures
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Introduction to GEP-Good Engineering Practices
 GEP means established engineering methods/standards that are applied
throughout the project life cycle to deliver appropriate, cost effective
solutions of manufacturing plant (Utility section-Air/water/equipments)
 Air lock is an enclosed space with two or more doors, which is interposed
between two or more rooms for the purpose of controlling the air flow
between those rooms when they need to be entered.
Types of Airlocks
 Cascade airlock: High pressure on one side of the airlock & low pressure
on the other.
 Sink Airlock: Low pressure inside the airlock & high pressure on the both
outer sides.
 Bubble Airlock: High pressure inside the airlock & low pressure on both
outer sides.
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Principles of GMP
 Good manufacturing practices (GMP) is a system for ensuring that
products are consistently produced and controlled to quality
standards.
 The procedures employed to ensure that the drug product or
substance is manufactured under a quality management system and
meets the claimed requirements for purity, Identity, safety and quality.
 It is designed to minimize the risks involved in any pharmaceutical
production that cannot be eliminated through testing the final products.
The main risks is Unexpected contamination of products, causing
damage to health or even death. ii. Wrong labels on containers,
leading to patients getting wrong medicine. iii. Not enough or too much
active ingredients, resulting in ineffective treatment or adverse effects.
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Principles of GMP conti…
 GMP covers all aspects of production: from the starting materials,
premises and equipment to the training and personal hygiene for staff.
Detailed written procedures are essential for each process that could
affect the quality of the finished products. There must be system to
provide documented proof that correct procedures are consistently
followed at each step in the manufacturing of process – every time a
products is made.
 WHO has established detailed guidelines for Good Manufacturing
Practices. Many countries have formulated their own requirements for
GMP based on WHO. Others have harmonized their requirements, for
example in the Association of South-East Asian Nation (ASEAN), in the
European Union and through the Pharmaceutical Inspection Convention.
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Utilities
Buildings and
Facilities
Stability
Programs
Warehouse
Facilities
Manufacturing
Areas
Lab Controls
Investigations
IPQC areas
GMP
Training
Records and
Reports
Process
Controls
Ingredients
controls
Reworks
Sampling &
Dispensing
SOPs
Process
Validation
Cleaning
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Recent Advances in WHO TRS Guidelines
WHO TRS 970 (46th Report, 2012)
 New principles of GMP on Water for Pharmaceutical Use (WPU)
 Quality Risk management system
 Standards for quality of pharmacy services
 Updates on the pre-qualification of Quality control Laboratories, pediatric
medicines
 Sampling procedures for monitoring of market situations
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WHO TRS 970 (46th Report, 2012)




WPU- Water for Pharmaceutical Use
Water is most widely used substance, raw material or starting
material in the production, processing and formulation of various
dosage forms
Water has unique chemical properties due to its polarity and
hydrogen bonds. This means it is able to dissolve, absorb, adsorb
or suspend many different compounds
These include contaminants that may represent hazards in
themselves or that may be able to react with intended product
substances, resulting in hazards to health
Harm:- Damage to health, including the damage that can occur
from loss of product quality or availability. Whereas hazard is the
potential source of harm & severity is a measure of the possible
consequences of a hazard
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WHO TRS 970 (46th Report, 2012)
WPU- Water for Pharmaceutical Use conti…
 Control of the Microbiological quality of WPU is a high priority.
Some types of microorganism may proliferate in water treatment
components and in the storage and distribution.
 The materials that come into contact with WPU including pipe
works, valves, fittings, seals, diaphragms and instruments should be
selected to satisfy objectives like compatibility, prevention of
leaching and corrosion resistance.
 Smooth of internal finish:
 The internal material finish should have an arithmetical average surface
roughness of NMT 0.8 micro meter
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WHO TRS 970 (46th Report, 2012)
Water Purification systems (WPS)
 Specifications for water system equipment, storage and
distribution system should take into account for the following:
 Location of plant
 Extremes in temperature that the system will encounter
 The risk of contamination from leachates from contact
materials.
 The adverse impact of adsorptive contact materials
 Hygienic or sanitary design, were required
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WHO TRS 970 (46th Report, 2012)
Water Purification systems conti…
 Corrosion resistance
 Freedom from leakage
 A system configuration to avoid proliferation of microbiological
organisms
 Tolerance to cleaning and sanitizing agents (thermal and/chemical)
 The sanitization strategy
 The system capacity and output requirements
 The provision of all necessary instruments tests and sampling point
to allow all the relevant critical quality parameters of the complete
system to be monitor
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WHO TRS 970 (46th Report, 2012)
Water system Qualification (WS Qualification)
 WHO document does not define the standard requirements for the
conventional qualification stages DQ, IQ and OQ but concentrates on the
particular PQ approach that should be used for WPU system to
demonstrate their consistent and reliable performance
 A three phase approach should be used to satisfy the objective of proving
the reliability and robustness of the system in service over an extended
period
• Phase 1:– Sample daily or continuously monitor the incoming feed water to verify its quality.
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Water system Qualification conti…
• Phase 2:– A further test period of two weeks should be spent carrying out further
intensive monitoring while deploying all the defined SOPs after the
satisfactory completion of phase 1. (The sampling system is same as
applied to phase 1).
– This approach demonstrates consistent operations within the established
range and also production and delivery of water of the required quantity
& quality when the system is operated in accordance with SOPs.
• Phase 3:– Typically runs for one year after completion of phase 2 to demonstrate
reliable performance over an extended period and also to ensure that
seasonal variations are evaluated.
– The sample locations, sampling frequencies and tests should be reduced
to the normal routine pattern based on established procedures proven
during Phase 1 & Phase 2.
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WHO TRS 970 (46th Report, 2012)
Inspection of water systems (WS Inspection)
The following list identifies items and a logical sequence for a
WPU system inspection or audit
 A current drawing of the water system showing all equipment in the
system from the inlet to the points of use along with sampling
points and their designations;
 Approved piping drawing (e.g orthographic and/ or isometric)
 A sampling and monitoring plant with a drawing of all sample points
 Training programme for sample collection and testing
 The setting of monitoring alert and action levels
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WHO TRS 970 (46th Report, 2012)
Inspection of water systems conti…
 Monitoring results and evaluation of trends
 Inspection of the last annual system, review
 Review of any changes made by the system since the last audit
and a check that the change control has been implemented
 Review of deviations recorded and their investigation
 General inspection of system for status and condition
 Review of maintenance, failure and repair logs
 Check calibration and standardization of critical instrument
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Recent Advances in WHO TRS Guidelines
WHO TRS 961 (45th Report, 2011)
 Release procedure of ICRS (International Chemical Reference
Substances)
 Good practices for microbiology laboratories
 Good practices for Blood establishments s
 Good practices for HVAC for non-sterile dosage forms
 Good practices on Transfer of Technology in pharmaceutical
manufacturing
 Standards for quality of pharmacy services
 Guidelines for preparing a Laboratory Information File (LIF)
 Guidelines for drafting a Site Master File (SMF)
 Storage practices for Biological products
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Recent Advances in WHO TRS Guidelines
WHO TRS 957 (44th Report, 2010)
 QC for Radio-Pharmaceuticals
 Good practices for Quality Control Laboratories
 GMP for APIs
 GMP for pharmaceutical products containing hazardous
substances.
 Good distribution practices for pharmaceutical products
 Guidelines on the re-qualification of pre-qualified dossiers
 Guidelines for the preparation of CRO master file.
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WHO TRS References since 1965
• WHO Expert
Preparations-
Committee
on
Specifications
for
Pharmaceutical
TRS 970, 46th report 2012; TRS 961, 45th report 2011
TRS 929, 39th report 2005; TRS 937 40th report 2006; TRS 943 41st
Report 2007; TRS 948 42nd Report 2008; TRS 953 43nd Report 2009; TRS
957, 44th report 2010; TRS 953, TRS 917 38th Report 2003; TRS 908 38th
Report 2003; TRS 902 36th report 2002; TRS 885 35th Report 1999;TRS
863 34th Report 1996; TRS 834 33rd Report 1993; TRS 823 32st Report
1992; TRS 614 26th Report 1977; TRS 645 27th Report 1980; TRS 681
28th Report 1982; TRS 704 29th Report 1984; TRS 748 30th Report 1987;
TRS 790 31st Report 1990; TRS 567 25th Report 1975; TRS 487 24th
Report 1972; TRS 463 23rd Report 1972; TRS 418 22nd Report 1971; TRS
307 21st Report 1965
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Other References
• WHO Expert Committee on Specifications for Pharmaceutical Preparations
special amendments
• Drugs and Cosmetics Act, 1940 & Rules 1945 there under and also
published recent amendments by Govt. of India.
• ICH Guidelines
• USFDA Guidance Document for OOS.
• ISPE Guidelines for Good Engineering Practices.
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GxP
 The FDA initiatives "Pharmaceutical cGMPs for the 21st
Century: A Risk-Based Approach" concerns the regulation of
pharmaceutical manufacturing and product quality with an
aim to focus GMP-enforcement on high-risk products. It aims
at encouraging the adoption of modern and innovative
manufacturing technology, and to develop consistent and
predictable policies for ensuring drug quality and safety.
Similar approach is being adopted in other FDA regulated
industries like medical devices and biotechnology as well as
for laboratory (GLP) and clinical environments (GCP).
GxP= GMP+GLP+GCP+GEP+GSP+GDP
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Life is like a game & juggling some five balls in the air.
They are
Work, Family, Health, Friends & Spirit
You will soon understand that work is a rubber ball. If you
drop it, it will bounce back but the other four balls-family,
Health, Friends & Spirit are made up of glass. If you drop
one of this they will be irrevocably scuffed, damaged,
marked, nicked or even shattered. They will never be the
same. You must understand that and strive for it.
Work efficiently during office hours and leave on time. Give
the required time to your family, friends & have proper
rest.
“Value has a value only if its value is valued”
Thank you