Schedule L1- How it may impact you

1. Schedule L1- How it may impact you IPA Bangaluru Branch 4th September Bangaluru Kapil Bhargava Dy. Drugs Controller (I) retired Mumbai

2. Introduction For GLPs a newly introduced Schedule in • Drugs and Cosmetics Rules • It is applicable from 01.11.2010 • WHO has also introduced a new Annexure and has been titled with similar words – popularly known as GLP and in in draft form • Another WHO draft only on microbiology Labs kplbhargava@yahoo.co.in

3. Presentation shall cover • Salient features of this schedule • How on existing laboratories it may have effect • The different provisions (already non existing ones) to be added now • Difficult to understand requirements • Their logic • Any Correction are needed or clarifications required by regulatory bodies kplbhargava@yahoo.co.in

4. General • a) The laboratory or the organization of which it is a part must be an entity that is legally authorized to function and can be held legally responsible. • Legal Status of the laboratory attached to a manufacturing unit kplbhargava@yahoo.co.in 4

5. Personnel • (c) Laboratory management shall have a qualified individual to be known as quality manager or technical manager for carrying out all technical activities and for the implementation of documented quality system and shall report to the top management directly. • quality manager or technical manager for carrying out all technical activities! kplbhargava@yahoo.co.in 5

6. Personnel • (d) The quality manager shall prepare a schedule for technical audit of the laboratory for GLP compliance by an expert appointed by the top-management other than the in charge of the laboratory and shall ensure the maintenance of documented quality system as per quality, manual • GLP compliance by an expert appointed by the top-management other than the in charge of the laboratory – An outside auditor is must! kplbhargava@yahoo.co.in 6

7. 2. Premises • (a) (i) the laboratories shall be designed, constructed and maintained so as to prevent entry of insects and rodents besides cross contamination • besides cross contamination – • Cross contamination in the laboratory is to be avoided • Two different samples cannot be handled by an analyst and so on.. kplbhargava@yahoo.co.in 7

8. HVAC • (iv) air ventilation system shall ensure dust free environment • Installation of HVAC is essential now kplbhargava@yahoo.co.in 8

9. HVAC • (b) The laboratories shall be provided with adequate lighting and ventilation and if necessary air- conditioning to maintain satisfactory temperature and relative humidity that will not adversely affect the testing and storage of drugs or the accuracy of the functioning of the laboratory equipments or instruments. kplbhargava@yahoo.co.in 9

10. Premises / Work Area • (d) Tabletops shall be constructed with acid, alkali, and solvent resistant material and shall be smooth and free from crevices as far as possible - • Permitting some crevices on table tops? kplbhargava@yahoo.co.in 10

11. Premises • (e) All bio-medical laboratory waste shall be destroyed as per the provisions of the Bio-Medical waste (Management and Handling) Rules, 1996. kplbhargava@yahoo.co.in 11

12. RS/WRS & Secondary Std. • (f) Adequate space with proper storage conditions in the laboratory shall be provided for keeping reference and working standards and be maintained by the quality control department. • Standard Operating Procedure (SOP) for the maintenance of reference standards and evaluation of Working and Secondary standards… kplbhargava@yahoo.co.in 12

13. Premises – Sterility Test Area • (g) The air circulation is maintained in the area where sterility test is carried out as per Schedule ‘M’ • Schedule M does not prescribe fair circulation for testing laboratory, it is there for mfg. areas • (h) Bio-burden shall be routinely maintained in the controlled and uncontrolled area. (e.g. air locks) • It is not good to “maintain” bio-burden kplbhargava@yahoo.co.in 13

14. Animal House:- • (i) Animal House shall have the approval of the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA). kplbhargava@yahoo.co.in 14

15. Animal House • (ii) Designed in such a way that there is an arrangement to quarantine the new animals procured or purchased and have a provision for clean corridor and dirty corridor • Clean and Dirty corridor -- Very difficult provision for already existing animal houses particularly those attached to small size mfg. units kplbhargava@yahoo.co.in 15

16. Personnel • (c) Head of the laboratory must be of high professional standing with experience in drug analysis and laboratory managements who is responsible for…. : • high professional standing!! kplbhargava@yahoo.co.in 16

17. Personnel • (iv) taking final responsibilities for recommending any regulatory action in the event of non-compliance of tested samples • Head of the laboratory is now expected to recommend to management the regulatory action to be taken for non compliances !! kplbhargava@yahoo.co.in 17

18. Equipment • (f) A progress register for non-functional equipments and action for procurement of spares and accessories, monitoring thereof, shall be maintained. kplbhargava@yahoo.co.in 18

19. Equipment • (g) A Standard Operating Procedure for preventive maintenance of machine or equipment or apparatus shall be prepared by the laboratory. kplbhargava@yahoo.co.in 19

20. Equipment • (h) Other equipment such as burettes, pipettes, volumetric flasks, weight boxes, thermometers, etc., shall be thoroughly checked for calibration before acceptance for use. • shall be thoroughly checked for calibration before acceptance for use – This means that supplier’s certificate is not acceptable and pipettes and volumetric flasks are to be calibrated in-house! kplbhargava@yahoo.co.in 20

21. Equipment • (i) Maintenance procedure in the form of Standard Operating Procedures must be prepared and regular servicing must be performed by the maintenance engineer or specialist • Requirement of a maintenance engineer is now essential kplbhargava@yahoo.co.in 21

22. Equipment • (l) Autoclaves must meet the requirements described for operations, safety and validation procedures, and the validation carried out by the laboratory shall be recorded kplbhargava@yahoo.co.in 22

23. Reagents • (d) Containers of stock solutions and of standard shall bear the following details- • (i) • (ii) • (iii) “use before date” depending upon the stability of the solution; and • (iv) standardization records - It is very difficult to mention standardization records on stock solution containers ! kplbhargava@yahoo.co.in 23

24. Good house keeping and safety • (iv) the laboratories shall have adequate first aid kit and fire fighting equipments located at the right places and the staff must be familiar and trained with the use of fire fighting equipment including fire extinguishers, fire blankets and gas masks. • fire blankets and gas masks are essential now kplbhargava@yahoo.co.in 24

25. Reference Materials • 8(a) Reference materials are necessary for the testing and, or calibration, validation or verification of a sample or of equipment, instruments or other devices and all such materials shall be traceable to agency authorized by Government of India or any other International body • Difficult to comply! kplbhargava@yahoo.co.in 25

26. Working Standards • (b) The laboratory shall prepare working standard by comparing with the reference standards and shall be routinely checked for their purity by selecting parameters such as identity, loss on drying or on water, impurity and assay, etc. • Difficult to comply! kplbhargava@yahoo.co.in 26

27. Reference Material • (c) Wherever, any new reference material is received by the laboratory, a code number shall be assigned and this code number shall be quoted on the laboratory note book and analytical work sheet. • The working standard shall also be provided with identification code. • I did not understand the purpose of this requirement kplbhargava@yahoo.co.in 27

28. Working Standards • (e) All working standards shall be checked at appropriate intervals or before use to ensure that it has not deteriorated or decomposed during storage. • Checking deterioration or decomposition frequently or prior to use is very difficult and also time consuming . It may not serve the intended purpose . This may be OK for PTLs or Government Laboratories kplbhargava@yahoo.co.in 28

29. Microbiology Cultures • (b) if the cultures have become non-viable or mutant, proper procedure shall be followed to destroy these cultures by autoclaving under an authorized personnel for biological testing. Preferably not more than five passages may be prepared. • This is to be more scientific – Checking culture purity is to be emphasised – more for Assay Cultures and less for limit test cultures kplbhargava@yahoo.co.in 29

30. Microbiology Work • (c) All activities be carried out in a aseptic area by authorized person. •  Now aseptic area is needed for all microbiological work – In existing laboratories Aseptic area is difficult to create (or upgrade) kplbhargava@yahoo.co.in 30

31. Microbiology Work • (d) The laboratories shall perform standard biochemical tests on the sub-culture as given in literature to ensure their viability • Each subculturing all biochemical tests are expected to be carried out • Viability can be tested by other means too • This provision is more suited for preparative work kplbhargava@yahoo.co.in

32. Quality system •  The quality system shall be designed to ensure the following objectives:- • (a) the measurements and calibrations shall fully conform to the compendial requirements and methods demonstrably based on validation protocols are followed • Method Validation for all the analytical methods is compulsory now!! • No references in IP or Drug Rules are available kplbhargava@yahoo.co.in 32

33. Internal quality system audits • (a) Internal audits are done…. to comply with requirements of regulatory authorities. • Some Check-list from Govt. is needed • Internal audits shall be carried out by trained and qualified personnel who are independent of the activity to be audited • In smaller labs this too is difficult for compliance kplbhargava@yahoo.co.in 33

34. SOPs for: • (i) sample handling and accountability; • (ii) receipt identification, storage mixing and method sampling of the test and control articles; • (iii) record keeping, reporting, storage and retrieval of data; • (iv) coding of different studies, handling of data including use of computerized data system; kplbhargava@yahoo.co.in 34

35. SOPs for: • (v) operation of technical audit personnel in performing and reporting audits, inspections and final report reviews; • (vi) routine inspection of cleaning, maintenance, testing, calibration and standardization of instruments; • (vii) action to be taken in respect of equipments failure; • (viii) analytical data methods; • (ix) the raw data; • (x) data handling and storage retrieval kplbhargava@yahoo.co.in 35

36. SOPs for: • (xi) • (xii) • (xiii) • (xiv) • (xv) maintenance of sterility room (i.e. constant maintenance and monitoring of Aseptic condition of sterility room) • (xvi) • (xvii) • (xviii) monitoring of testing of samples – I have not understood this SOP • (xix) methods of retention of unexpended samples, their location, maintenance and disposal – easy to write SOP but difficult to comply • (xx) document control kplbhargava@yahoo.co.in 36

37. SOPs for: • (xxi) redressal of technical complaints; • (xxii) housing-keeping • (xiii) corrective and preventive action; • (xxiv) working procedure (test methods); • (xxv) calibration Manual; and • (xxvi) training manual. kplbhargava@yahoo.co.in 37

38. Protocols Archives • (b) All updates and corrections must be noted in the master volumes of Pharmacopoeias to prevent the use of obsolete sections; supplement and addendum shall also be made available in the laboratory. • (c) The specification archive shall contain the following:- kplbhargava@yahoo.co.in 38

39. Protocols Archives • (i) • (ii) a file on patent and proprietary medicines (non- pharmacopoeial) test methods to specifications prepared and validated by the manufacturer or by the laboratory itself. • The test methods shall be submitted to the concerned Drugs Control Authority. • The validated test methods developed by the manufacturer or the laboratory shall stand to the requirements of compendial parameters in regards to its precision, accuracy, reproducibility, specificity, linearity, and ruggedness etc. kplbhargava@yahoo.co.in 39

40. Storage and archival • (a) The residual sample shall be retained in proper storage condition for a period of one year after the finial report. kplbhargava@yahoo.co.in 40

41. Storage and archival • (b) The laboratory must establish and maintain procedures for the identification collection, indexing, retrieval, storage, maintenance, and disposal of all quality documents. kplbhargava@yahoo.co.in 41

42. Storage and archival • ©…. The archive shall provide a suitable environment that will prevent modification, damage, or deterioration and/ or loss • (d) The condition under which the original documents are stored must ensure their security and confidentiality. kplbhargava@yahoo.co.in 42

43. Storage and archival • (e) Paper documents shall not be kept for long periods under high humidity and raw data in the form to tape and discs are to be preserved with care • (f) In case of storage of only optical disc, the life of disc shall be longer than the storage time. kplbhargava@yahoo.co.in 43

44. Storage and archival • (g) Raw data on thermal paper might fade away with time; therefore, a photocopy of the thermal paper shall also be retained in the archive. • (h) Time for which records are retained shall be prescribed in the documents.” kplbhargava@yahoo.co.in 44

45. Summarizing • On reading the GLP Schedule one may get impression that it has been designed with PTLs and other such laboratories in mind • All provisions here may not be relevant to laboratories attached to manufacturing units • Provisions in Schedule L1 are legal requirement and are to be complied with strictly therefore clarifications may be sought for provisions which are either not clear or not relevant kplbhargava@yahoo.co.in 45

46. My references were • Schedule L1, Schedule M, WHO TRS and other WHO documents • Support from my colleagues, ex colleagues and professional in the industry Thanks for your attention kplbhargava@yahoo.co.in

47. Questions? kplbhargava@yahoo.co.in