“WHO TRS Requirements on Pharmaceuticals Moving in International Commerce”

Dr. A. Ramkishan Deputy Drugs Controller (India)-(Incharge)

Office of Deputy Drugs Controller (India), Zonal OfficeCentral 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 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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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 Manipulation (1989)

No Objection Certificate for Clinical Trial & also r-DNA strains,

DCC Drug Consultative Committee (since 1951)

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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Industry size : 25.8 Bn USDExports : 13.2 Bn USD

Imports: 3.52 Billion USDIndustry 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 BnExport of Vaccines- US $507.9 million (US $ 42 Bn by year 2015)

Manufacturing Facilities 172 US FDA ApprovedIndia Stood First Globally with 2759 DMF filling Out of 7886 DMFs

US Pharmacopoeia has office in Hyderabad, IndiaUSFDA has country office in Delhi, Mumbai

9,000 manufacturing units in the country600,000 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 countriesVaccines from India are exported to more than 151 countries

Goa

New Delhi

Chennai

CDSCO North Zone (Ghaziabad)

Kolkata.

CDSCO West Zone (Mumbai)CDSCO South Zone (Chennai)CDSCO East Zone (Kolkata)

CDSCO, HQ

• HyderabadAhmedabad

*New Zonal Offices : 2 (Ahmedabad & Hyderabad)*Sub- Zonal Office : 3*Port Offices/Airports : 11*Central Laboratories : 6

35 SLAs= 29 States+ 6 UTs

Bengaluru

Geographical Location of CDSCO

Chandigarh

J&KHQ

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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-DNAproducts & 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 or Reconstruction of all activities activities (Direct confirmation) (Indirect confirmation)

Judgment taken Accept / Reject

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GLP

Internal Quality System Audits

General Requirements Premises

Personal

Equipments

Chemicals and Reagents

Quality SystemMicrobiological Cultures

Reference Materials

Maintenance, Calibration, and

Validation of Equipments

Good House Keeping and SafetyManagement Review

Standard Operating Procedures

Protocols and Specifications Archive

Raw Data

Storage and Archival

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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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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

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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Principles of GMP conti…

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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

Recent Advances in WHO TRS Guidelines

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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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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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WHO TRS 970 (46th Report, 2012)

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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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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WHO TRS 970 (46th Report, 2012)

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

Recent Advances in WHO TRS Guidelines

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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.

Recent Advances in WHO TRS Guidelines

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WHO TRS References since 1965 • WHO Expert Committee on Specifications for Pharmaceutical

Preparations-

TRS 970, 46th report 2012; TRS 961, 45th report 2011TRS 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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• 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.

Other References

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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 & SpiritYou 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