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1. “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 1

2. Disclaimer The views expressed in this presentation are my own, and I have no financial interests to disclose. 2

3. 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 3

4. 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. 4

5. 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. 5

6. 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. 6

9. 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. 9

10. Snapshot - Indian Pharmaceutical Industry

12. New Delhi Goa Chennai CDSCO, HQ Geographical Location of CDSCO HQ CDSCO North Zone (Ghaziabad) J&K CDSCO West Zone (Mumbai) Chandigarh CDSCO South Zone (Chennai) Kolkata . Ahmedabad CDSCO East Zone (Kolkata) • Hyderabad *New Zonal Offices : 2 (Ahmedabad & Hyderabad) *Sub- Zonal Office : 3 *Port Offices/Airports : 11 *Central Laboratories : 6 Bengaluru 35 SLAs= 29 States+ 6 UTs 12

14. 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 14

15. 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 15

16. 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. 16

17. 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. 17

18. Pharmaceutical product Submitted to regulatory authority Verification Repetition of experiment or Reconstruction of all activities activities (Direct confirmation) (Indirect confirmation) Judgment taken Accept / Reject 18

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20. GLP Concerns as Per Schedule L1 (Rule 74, 78 & 150E), Drugs & Cosmetics Act 1940 General Requirements Storage and Archival Premises Raw Data Personal Equipments Protocols and Specifications Archive Chemicals and Reagents Standard Operating Procedures GLP Good House Keeping and Safety Management Review Maintenance, Calibration, and Validation of Equipments Internal Quality System Audits Reference Materials Quality System Microbiological Cultures 20

21. 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. 21

22. 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.

23. 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.

24. GMP Concerned with………..

25. 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 25

26. 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 26

27. 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 27

28. 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 28

29. 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 29

30. 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. 30

31. 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. 31

32. 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 32

33. 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 33

34. 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 34

35. 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. 35

36. WHO TRS References since 1965 • WHO Expert Committee on Specifications for Pharmaceutical Preparations- • 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 36

37. 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. 37

38. 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

39. 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”

40. Thank you