“ Good Laboratory Practices and Requirements of Premises & Equipments”

1. “Good Laboratory Practices and Requirements of Premises & Equipments” Presentation by: Dr. A. Ramkishan Asst. Drugs Controller (India) Govt. of India 1

2. Seminar Overview • Schedule L-I notification and D & C Act Rules • Management and Infrastructure (Organization & Management, Premises, Personnel, Equipments) • Materials, Equipments, Instruments & Other Devices (Chemicals & Reagents, Good Housekeeping & Safety, Maintenance, Calibration & Validation of Equipments, Reference Materials/Substances, Microbial Cultures) • Quality Management System • Working Procedures (SOPs, Protocols & Specifications Archive, Raw data, Storage & Archive) • Internal Quality System Audits • Management Review • Safety (General Rules) • India Advantage & Challenges 2

3. Evolution of Indian Drug Legislation Objective The Objective of Drugs & Cosmetics Act 1940 is to ensure that public are supplied with Quality, Purity, Identity, Safety and efficacy of Pharmaceutical Products & Cosmetics. 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. 3

4. Evolution of Indian Drug Legislation Cont.. 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 & Rules 1945 there under. 4

5. Functions of CDSCO Functions of CDSCO Approval of new drugs and clinical trials Import Registration and Licensing Licensing of Blood Banks, LVPs, Vaccines, r-DNA products & some Medical Devices Amendment to D &C Act and Rules Banning of drugs and cosmetics Grant of Test License, Personal License, NOCs for Export Testing of Drugs 5

6. Functions of State Licensing Authorities 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 6

7. CDSCO – Geographical Location of 6 Zonal Offices New Delhi Mumbai Chennai CDSCO, HQ CDSCO North Zone (Ghaziabad) CDSCO West Zone (Mumbai) CDSCO South Zone (Chennai) Ahmedabad* . CDSCO East Zone (Kolkata) Kolkata New Zonal Offices – Ahmedabad & Hyderabad Sub- Zonal Offices : 2 Port Offices/Airports : 7 Laboratories : 6 • * Hyderabad 29 States 6 Union Territories 7

8. Evolution of Indian Drug Legislation Responsibilities Cont.. 8

9. Implementation of Schedule L-I • The draft GLP published dated 13th October 2006 inviting objections & suggestions from Stake holders. • And, whereas, objections and suggestions received from the public on the said draft rules have been considered by Govt. of India. • Now therefore, in exercise of the powers conferred by the sections 12 & 33 of D & C Act, the Central Government after consultation with the DTAB, hereby made the rules called as D & C (3rd amendment) Rules 2008. • The Drugs and Cosmetics Rules were amended to incorporate Schedule L-I on GLP and Requirement of premises and equipments published under notification GSR 780 (E) dated 10th November 2008 (File No. X-11014/3/2006-DFQC). 9

10. Implementation of Schedule L-I Cont.. • A period of two years was granted for the Pharma industry to make necessary arrangement to comply with the requirement of Sch. L-I before these are made mandatory. • Accordingly the notification mentioned that these Rules will be effective from first day of November, 2010. • The labs are required to comply all the GLP norms mentioned in the Schedule L-I of D & C Act a per Rule 74, 78 & 150-E to cover quality system/SOPs, equipment calibration/validation, reference materials, reagents, staff, testing procedures, results record & computerization, personnel & environmental safety, data integrity, including archiving. • Internal quality system audits are required to put in practice to verify that the operations conduct in the laboratories comply with the requirements of quality system. • State licensing authorities may ensure that the provisions under Sch. L-I are implemented in the testing laboratories set up by the manufacturers for in house testing and approved testing laboratories. 10

11. D & C Act 1940 and Rules there under • Schedule L ,1979-rule 65(9) GSR 1241 dated 15.09.1979 & 97 GSR 592 (E) dated 13.08.2008 are omitted. • Schedule L-I 2008 (3rd amendment) prepared on GLP for various labs covered the rules- 74,78 & 150-E of D & C Act . • Rule 74 (GSR 218 (E) dated 28.03.2001) deals with condition of license {Form 25 (other than C, C1 & X drugs) & 25-F (Sche. X Drugs)}. • Rule 78 (GSR 462 (E) 26.06.1982 & omitted, revised w.e.f. 01.11.2010) deals with conditions of license {Form 28 (for C & C1 Drugs excluding Sche. X) , 28-B (for C, C1 & X Drugs) or 26-D (renewal of Lic. for AUSH Drugs)}. • Rule 78(p) deals with compliance of GLP & GMP. • Rule 78(m) deals with reference samples for proper storage • Rule 150-E deals with conditions of approval 11

12. D & C Act 1940 and Rules there under cont.. • Rule 150-B deals with application for grant of approval for testing drugs/cosmetics in Form 36. • The labs shall be made an application in Form 36 to SLA for necessary approval with fees Rs.6000/- for C,C1 drugs and Rs.1500/- for other than C&C1 drugs/Cosmetics (as per Rule 150-B). • Rule 150-C deals with approval for carrying out such tests of identity, purity, quality & strength of drugs or cosmetics shall be granted in Form 37. • An approval granted in Form 37 or renewed in Form 38 unless sooner suspended or withdrawn shall be valid for a period of five years on and from the date on which it is granted or renewed (Rule 150-D). • The approved institution shall furnish reports of the results of tests or analysis in Form 39 as per Rule 150-E of D & C Act 1940. 12

13. D & C Act 1940 and Rules there under cont.. • Inspection before grant of approval (Rule 150-F) and inspection team consisting of CDSCO & SLA, who shall examine the premises, equipments, staff, testing procedures intended to be used for testing of Drugs & Cosmetics. • Rule 150-G deals with report of inspection • Rule 150-H deals with procedures of approving authority (SLA) shall grant an approval in Form 37. • Rule 150-J deals with renewal of approval in Form 38 • Rule 150-K deals with suspension & withdrawal of approvals • Rule 150-I deals with further application after rejection in Form 37 • A Licensee (PTL/Group/National/QC labs) shall maintain an inspection book in Form 35 to record the observations if any by the FDA/CDSCO inspectors. 13

14. Definition of 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. 14

15. Definition of Quality Control • Quality Control Laboratory: All measures taken, including the setting of specifications, sampling, testing and analytical clearance, to ensure that raw materials, intermediates, packaging materials and finished pharmaceutical products conform with established specifications for identity, strength, purity & other characteristics. • Quality:- The degree to which a set of inherent properties of a product, system or process fulfills requirements. (ICH Q6a) • Risk:- The combination of the probability of occurrence of harm & the severity of that harm (ISO/IEC Guide 51) • 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 15

16. Role of GLP Inspectors • For a FDA/CDSCO inspector it should be possible to look at the documentation and to easily find out • who has done a drug sample testing,  • how the sample testing was carried out,- • which procedures have been used, and • whether there has been any problem and if so • how it has been solved. • The FDA inspectors should look at the possibility for a third party to reconstruct the whole drug samples testing plan & second issue can be looked at as accountability for mistakes of above plan & thirdly GLP increases awareness for quality and transparency of the analysis of different samples conducted at their laboratory. • GLP Compliance as per Schedule L-I of Drugs & Cosmetics Act. 16

17. Role of GLP Inspectors Cont.. • Basic research, Disease Discovery & Drug Discovery are not regulated for GLP. • The GLP regulation starts from Pre-clinical development to QC Laboratories. • Clinical trials are regulated by good clinical practice regulations and manufacturing through GMPs. • Characteristic for GLPs is that they are study based where as GMPs are processed based 17

18. Elements of GLP • To a large range of laboratory related issues that can shortly be characterized as follows 1- Laboratory infrastructure and personnel. 2- Laboratory methodologies & reference values. 3- Laboratory equipment & maintenance. 4- Test result records & computerization. 5- Quality system (internal audits, management review). 6- Function of annual units and experiments. 7- SOPs & General safety. 8- Storage and archival. 18

19. Organization & Management • The laboratory or the organization of which it is a part must be an entity that is legally authorized to function & can be held legally responsible. • It is the responsibility of the management to ensure that the laboratory carry out its testing, calibration, validation & all other technical activities in such a way as to meet GLP requirements as per Schedule L-I • The laboratory should be organized and operate so as to meet the requirements of Schedule L-I. • The laboratory should have a qualified individual to be known as quality manager or technical manager with the authority and resources needed for carrying out all technical activities and for the implementation of documented quality system to report directly to top management. • The quality manager shall prepare a Schedule for technical audit of lab for GLP compliance as per quality manual. 19

20. Premises • The laboratory facilities shall be designed, constructed and maintained so as to prevent entry of insects and rodents besides cross contamination. • The lab interior surface (walls, floor and ceilings) should be smooth and free from cracks and permit easy cleaning/disinfection. • Adequate area should be provided for equipments for carrying out different tests but also for utilities like water, gas and power. • The lab should have air ventilation system to ensure dust free environment. • The lab should be provided with adequate lighting and ventilation and if necessary AC to maintain proper temperature/Rh that will not effect the testing and storage of drugs or accuracy functioning of equipments. • The lab should have proper drainage system to avoid water logging. • Tabletops shall be constructed with acid, alkali and solvent resistant material (Free from crevices). 20

21. Premises Cont.. • All the laboratory waste material generated, before, during & after testing of different pharmaceutical products/cosmetics should be destroyed as per Bio-Medical waste rules 1996 (management & handling). • The laboratory should ensure that environmental conditions are monitored, controlled & documented. • Adequate area should be provided for storage of reference, working standards & thereof specific SOP should be prepared by the laboratory. • If the laboratory engaged with microbiological testing, BET testing & sterility testing should meet the requirements of air circulation (HVAC system) with requisite class condition as per the revised Schedule M of D & C Act 1940. • The bio burden levels should be routinely monitored in the airlocks provided for controlled & un-controlled areas. 21

22. Premises Cont.. • The Lab should have proper area for animal house and should have the approval of the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA) from regional office of ethics animal committee. • The lab should have proper segregation for quarantine the new animals procured are purchase and have a provision for clean corridor and dirty corridor. • The disease animals shall be properly diagnosed with proper record of their treatment. • Different types of animals should be housed separately with proper identification. • The Lab should have air conditioner (AC) for animal house (Temp./RH). • The Animal house should be isolated from the laboratory with separate entrance if applicable. 22

23. Personnel • The laboratory should have sufficient staff with necessary qualification, training, experience for their assigned functions and thereof training records are maintained. • The head of the laboratory must be off high professional standing with experience for testing of drug samples & lab management is responsible for ensuring control and maintenance of documents including quality system. • The laboratory should have proper planning and organizing the audit of quality system to take care of CAPA. • CAPA resulting from the investigation of complaints, product rejections, non conformances, recalls, deviations, audits, regulatory inspections & findings, trends from process performance & product quality monitoring. The objective of CAPA is determining the root cause of deviation. • Corrective Action: Action to eliminate the cause of a detectable non-conformity or other undesirable situation. Note: Corrective action is taken to prevent recurrence whereas preventive action is taken to prevent occurrence (ISO 9000:2005) 23

24. Personnel cont… • Preventive Action: Action to eliminate the cause of potential non-conformity or other undesirable potential situation. Note: Preventive action is taken to prevent occurrence whereas corrective action is taken to prevent recurrence (ISO 9000:2005). • The laboratory should have proper planning for investigation of technical complaints including NSQ reports for regulatory action. 24

25. Equipments • The laboratory should have the required equipments for carrying out the different activities within the lab. • The analytical instruments should be kept in dust free environment with proper control of temperature and humidity. • The equipment should be kept under hygienic conditions and tidy (logical/orderly/arranged/uncluttered) at all times. • The laboratory should have proper calibration plan and validation plan for equipments provided to carry out at specified regular intervals and records of such calibration/validation reports be maintained. 25

26. Equipments cont... • The records should be maintained for all the equipments consisting of: • Name of Equipment or Machine or Apparatus; • Manufacturer’s name, Model number and type of identification; • Serial number; • Date on which equipment was received in laboratory; • Current location; • Condition when received (e.g. new, used, re-conditioned) • Copy of the manufacturer’s operating instructions; • Frequency of calibration; • Frequency of maintenance; • Log Book (Day to day entry including status of the equipment) • Staff responsible for monitoring the calibration and maintenance status of the equipment; • Calibrating records; • List of authorized users or operators, if any; • History of any damage, malfunction, modification or upgradation, repair and calibration; • List of spares and accessories, if any; 26

27. Equipments cont... • The laboratory should have separate register for defective equipments and also spare/accessories. • The lab. should have respective SOP’s for operation, performance, calibration & maintenance of equipments. • The lab. should have thorough checks for accuracy of important items like; burettes, pipettes, volumetric flasks, weight boxes, thermometers, etc., before use. • The lab. Should have competent person for handling and maintenance of equipments for services like; electricity, gas, water, steam and compressed air, etc. • The lab. should have well defined area for handling of hazardous solvents, reagents and chemicals with proper exhaust system and drainage system to avoid water logging inside the fume cupboard. • The lab. Should have proper log books, calibration chart reports, validation reports, engineering requisition slips for repair/modification if any, CAPA system, change management system and equipments service record’s. 27

28. Chemicals & Reagents • The laboratory should have proper plan for storage and handling of chemicals and reagents while preparing by taken into the consideration of Physico-chemical properties with proper status label. • Register should be maintained for standardization of stock solutions, standard solutions & volumetric solutions etc. • All the above said chemicals/ reagents should be off appropriate quality if required the Lab head must insist the COA, MSDS & reputation of suppliers in the market for their quality standards. • The labeling should be appropriate to meet the parameters like concentration, strength, storage condition, date of preparation, use before, standardization factor, sign of chemist etc. • Visual inspection is carried out for reagents if applicable. • Water should be considered as a reagent & appropriate water grade for specific test should be used as described in the various Pharmacopoeias or in approved tests when available. 28

29. Good House Keeping and Safety • Lab should prepare adequate poster displays, audio visual material, & conduct seminars and conferences for safety aspects. • Safety Data sheets must be available before testing is carried out. • Drinking, eating, smoking shall not be permitted in lab. • Laboratory staff must wear protective clothing including gloves, facemasks & eye protection when ever required. • Lab should be equipped with adequate number of fire extinguishers, fire blankets and gas masks etc. and also first aid kit. • Adequate training is must for staff for handling of safety equipments (emergency care and use of antidotes, handling cylinders of compressed gases). • Lab should have well defined SOP for safety, housekeeping, training, disposal of wastes (chemicals and biological), handling of corrosive materials (Hg, KCN, CNBr), infectious agents, mixing of water with Acids etc. 29

30. Maintenance, Calibration & Validation of Equipments • Maintenance: A procedure of inspecting, testing, and reconditioning a system at regular intervals according to specific instructions, intended to prevent failures in service or to retard deterioration. • Calibration: The process of determining the performance parameters of an artifact (object) , instrument, or system by comparing it with measurement standards (Accuracy & Precision). • Validation: Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results. • Validation vs. Qualification: The term qualification is normally used for equipment, utilities and systems, validation is normally used for processes in this sense, qualification is the part of validation. • Validation should be performed for new premises, equipments, utilities, systems, procedures & processes at periodic intervals & when major changes have been made. • Risk assessment approach should be used to determine the scope & extent of validation required. 30

31. Maintenance, Calibration & Validation of Equipments Cont.. • Qualification: Action of proving & documenting that any analytical equipment complies with the required specifications and performs suitably for its intended purpose. • The lab should have well defined SOP, qualification protocols, calibration schedule, appropriate methods and procedures for all tests or calibrations. • The lab should have records for calibration of equipments and other required documents including log books. 31

32. Quality management system • QMS: An appropriate infrastructure, encompassing the organizational structure, procedures, processes and resources, and systematic actions necessary to ensure adequate confidence that a product or service will satisfy given requirements for quality. • Quality System: Aggregate of the organizational activities, incentives, plans, policies, procedures, processes, resources, responsibilities, and the infrastructure required in formulating and implementing a total quality management (TQM) approach in a testing laboratory. • Quality Manual: A handbook that describes the various elements of the quality management system for assuring the quality of the test results generated by a laboratory. 32

33. Reference materials • Reference material: Material sufficiently homogeneous and stable with respect to one or more specified properties, which has been established to be fit for its intended use in a measurement processes . • Reference substance (or standard):An authenticated, uniform material that is intended for use in specified chemical and physical tests, in which its properties are compared with those of the product under examination, and which possess a degree of purity adequate for its intended use . • Primary reference substance (or standard): A substance that is widely acknowledge to possess the appropriate quality within the specified context, and whose assigned content is accepted without requiring comparison with another chemical substance. • Secondary reference substance (or standard):A substance whose characteristics are assigned and/or calibrated by comparison with a primary reference substance may be less than for a primary reference substance Note: often referred to as an “in-house” working standard. 33

34. Reference materials cont… • The lab should have necessary above said materials for testing, calibration, validation & verification of a sample or equipment or instrument or devices and such materials should be traceable to agency authorized by Govt. of India or international body. • The lab should prepare working standards by comparing with reference standards and shall be routinely checked for their purity, identity, loss on drying or on water, impurity and assay etc. thereof register should be maintained containing the details like source of supply, code number of reference material, date of receipt, batch number, storage condition, date of expiry, date of mfg. and other details like assay value, water content etc. • The working standards should be checked before use for testing to ensure that it has not deteriorated or decomposed during storage. • All the above said materials should be stored at appropriate storage conditions. • The lab should have proper microbial stock cultures & SOP should be prepared for Sub cultures, preservation, storage (NMT 5 passages). 34

35. Internal Quality System Audits • Laboratory Building & surroundings • Premises (including Animal House) • Personnel • Equipments • Chemicals & Reagents • Good House keeping and safety • Maintenance, calibration & validation of equipments • Reference materials • Microbial cultures • Aseptic areas (microbiology and sterility if applicable) • Quality system • Storage of starting materials and finished products • Documentation • Sanitation and Hygiene • SOP`s • Protocols & Specifications Archive • Raw data, • Storage & Archival • Corrective actions on previous reports 35

36. Protocols, Raw Data & Specifications Archive • Specification: A list of detailed requirements (acceptance criteria for the prescribed test procedures) with which the substance or pharmaceutical product has to conform to ensure suitable quality. • Protocol: Protocol is the documentation of all necessary specifications, calibrations, operating ranges, etc. Environmental factors such as temperature, humidity, barometric pressure, and other factors can often have effects on results. • Raw data :refers to the laboratory work sheet, note books or analysis sheet, records, memorandum, notes or extract copies thereof that may be the results of general observations and other activities of raw data includes written notes, photographs, software, drawings, spectral charts, computer print outs, dictated observations or recorded data from automated equipments, calibration records, record on receipt of animals, results of environmental monitoring etc. if any change in the raw data a single line shall strike through the data with signature and date. • The data integrity and security shall be maintained and not allowed for unauthorized person. 36

37. Storage & Archival • Residual sample shall be retained under proper storage condition for period of one year after the final report. • The lab should have well defined plan procedure for the identification, collection, indexing, retrieval, storage, maintenance and disposal of all quality documents. • The lab should have well archive for storage of documents to prevent modification, damage or deterioration or loss. • The original documents should be stored in secured area with restricted entry. • Paper documents should not be stored under high humidity. • A photocopy of the thermal paper shall be retained. • The documents should be retained as per the D & C Rules. 37

38. Advantage India • Proactive Government Policy • Fair & Efficient Judiciary • Established Pharma/biotech industry • Availability of Pool of Trained Man Power • Entrepreneur skills • Communication in English • Strength in IT, BT and PT • Potential Market • Requisite infrastructure • Communication System • Transport System • Well-established Hospitals in the Government and Private Sector facilitating clinical research for Biotech products 38

39. Challenges • Logistics • Communication skills • Training • Cultural Integration with Partners • Lack of interaction between academia, industry & Regulatory affairs • Lack of application of knowledge • Lack of Leadership 39

40. Ten Commandments of Success Speak to people:(There is nothing as nice as a cheerful greeting) Smile: (It takes 72 muscles to frown only 14 muscles to smile) Call people by name: (Everyone is pleased when you remember their name) Be friendly and helpful: (And others will respond in like manner) Speak and Act:(As if everything you do were a genuine pleasure) Be genuinely:(Interested in people) Be generous:(We praise, cautious with criticism) Be considerate: (With the feeling of others it will be appreciated) Be thoughtful: (Of the opinions of others, there are three sides to any controversy, yours, the other persons and the right one) Be willing: (To give service, what counts most in life is what we do for others) 40

41. What is Life? • 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 crushed. 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” 41

42. Thank You