LABORATORY EQUIPMENT AND ANALYTICAL OPERATIONS MANAGEMENT

1. LABORATORY EQUIPMENT AND ANALYTICAL OPERATIONS MANAGEMENT IFUDU COLETTE.N QUALITY ASSURANCE MANAGER NAFDAC CENTRAL DRUG CONTROL LABORATORY,YABA.

2. Learning Objective • To understand and appreciate laboratory equipment and analytical operations management.

3. Coverage • Laboratory Equipment management • Qualification and Calibration program • Examples of Equipment qualification requirements • Data Processing Equipment • Preventive maintenance • Trend Analysis • Documentation • Safety. • Analytical Operations management • Analysis planning • Factors in analysis planning • SOPs • Services and Supplies • Monitoring and Evaluation • Control of Data/ Data Integrity • Assuring the quality of Test Results • Reporting and review of Results

4. Laboratory Equipment Management • It is an essential part of the Quality Management System that there is documentary evidence to show that all equipment is working correctly at all times.

5. Laboratory Equipment Management • Acquisition- Appropriate and adequate number Laboratory Equipment • End-user Training • Qualification and Calibration Program • Preventive Maintenance plan • Documentation- SOPs , Equipment logs & records • Data processing Equipment

6. Laboratory Equipment • End-user input- Type of analysis, durability, accessibility, cost etc. • Adequate number of equipment required for correct performance of tests • Records of each item of equipment and it’s software maintained • All equipment uniquely identified

7. End-User training • Training on the proper and safe use -Hands-on & principles -Manuals -SOPs and Work Instructions -Done by original Equipment manufacturer and/or competent trainer. • Competency assessment. • Untrained personnel MUST not have access to laboratory Equipment.

8. Qualification and Calibration Programme Without calibration and qualification, you have no measurement and without measurement, you have no analysis or results

9. Qualification and Calibration • It is an essential part of the Quality Management System that there is documentary evidence to show that all equipment is working correctly at all times. • It may be appropriate to use “Risk Assessment” to determine the optimum “Frequency of Qualification”. • Qualification should be performed routinely (in line with a written plan). • The qualification performed should be in line with “International Standards” (BP/Ph Eur, IP, USP, EDQM).

10. Calibration • The process of verifying the capability and performance of an item of measuring and test equipment compared to traceable measurement standards. • Maintain traceability by keeping records and ensuring that all measuring equipment has been calibrated using certified traceable standards by the laboratory or calibration body traceable to SI unit.

11. Qualification and Calibration Program-2 • Establish qualification and calibration programs • Regular and scheduled qualification ,calibration, validation and verificationof all equipment, instruments and other devices used for measurement must be performed • Specific procedures for each type of equipment, instrument and other devices must be established, having regard to the extent of which they are used, verified and calibrated at regular intervals according to SOP.

12. Qualification and Calibration Program-3 • The major requirement is a set of SOPs which instructively and completely describe the process by which the Qualification tests will be performed and the analysts (or technicians) authorised to do the work. • The SOPs should describe when the qualification exercise is to be performed and how it will be reported. • The SOP should describe the process of checking the results obtained and the subsequent “Authorisation for Use” of the equipment.

13. Qualification and Calibration Program-4 • An authorisation to continue to use the instrument • The authorisation must be signed by a staff member defined in the SOP i.e. Analyst, Supervisor or Q.A. • A “sticker” on the instrument should show qualification status and date of last and next qualification. • Qualification is performed against a predetermined specification

14. Examples of Equipment qualification requirement • UV spectrophotometers -Full tests including stray light etc. 6 monthly and monthly test for Absorbance (Potassium Dichromate solution or filters) and wavelength accuracy (Holmium Filter). • IR spectrophotometers • Monthly check Wavelength accuracy and absorbance, equivalent to the requirements of the Ph Eur, using a “traceable” polystyrene film. • Auto-Titrators : The qualification test needs to be performed at least every 6 months. • It is necessary to confirm that measurement of delivered titrant is accurate and reproducible. The test can be performed by 3 titrations of NaOH against 3 (5 would be better for RSD determination) similar weights of dried potassium dihydrogen phthalate. • Calculate both accuracy and reproducibility of the titrations.

15. HPLC (further d details of how to perform the tests, including other detector systems are well described in the EDQM Guidelines.) • http://www.edqm.eu/site/quality-management-guidelines-86.html • Consult these documents to determine what is best for “Your Laboratory”. • Must qualify each module of Instrument independently. • Qualification is NOT method specific. • Qualification confirms that at a particular time an INSTRUMENT is working correctly and providing appropriate and trustworthy results. • System Suitability confirms that at a particular time an instrument using a particular METHOD will provide appropriate and trustworthy results. • Instrument Qualification not include either Column specification or methodology. • Injectors, Pumps, Column ovens and Detectors are confirmed to be working within pre-determined specifications.

16. Trend Analysis • The reporting sheets will often be complex documents (i.e. results for the qualification of HPLC apparatus). • It is not sufficient to simply compare the results obtained against those in the specification. The results must also be compared with those obtained previously. • Do the results show a positive or negative trend? • Do the results obtained during the last qualification exercise differ from those obtained previously? • Does the trend line indicate the instrument parameters have changed? • Is the apparatus still fit for use?

17. Trend Analysis • Trend Analysis is particularly important with instruments and apparatus which are checked or monitored on a daily basis i.e. Balances and pH meters. • You must be alert to changes and trends -Do the results indicate an abrupt change or a constant drift i.e. “Slope of pH calibration”. • Although the results may be within the requirements of the specification, the trend analysis may indicate the performance is “Suspect”.

18. Verification/monitoring • It is essential that Fridges, Freezers and Incubators are subjected to appropriate daily monitoring/checks • Wherever possible these devices should also be subjected to a mapping exercise • Appropriate specifications may be defined in the pharmacopoeia • Fridges: 2 - 8⁰C • Incubators: X +/- 2⁰C • Freezers: Not more than “Set Point” (theoretical) Temperature

19. Preventive Maintenance Plan • Preventative Maintenance is simply “mending it before it breaks” • Preventative maintenance is a requirement of WHO GPPQCL:2.3 The laboratory should establish, implement and maintain authorized written SOPs including, but not limited to, administrative and technical operations, such as:(k) preventive maintenance and verification of instruments and equipment. • When equipment is out of service it shall be isolated to prevent its use or clearly labelled or marked “OUT OF SERVICE” until it has been repaired • Calibration status of the Equipment are checked and shown to be satisfactory before equipment is returned to service. • .

20. It should be documented and preferably performed to pre-determined schedule. • Preventive Maintenance may be performed by In-House or by the instrument supplier/OEM • Annual Maintenance Contract- may include the provision of qualification. • In-house Instrument maintenance may be used. • It can include internal cleaning, calibration and realignment and lubrication, changing worn moving parts, filters ,seals, electrodes . • Analysts/Technicians performing Preventive Maintenance must be trained and competent.

21. Documentation- SOPs , Equipment logs & records • Procedures for safe handling ,transport ,maintenance • Work instructions for use • Records - Log book of daily use • Inventory and log book of checks,calibrations,maintenance,repairs--- • Calibration Certificates • History cards

22. Equipment log book • Maintain Instrument Logbooks. • Information on instrument use is easily traceable • Not mandatory., however, full traceability showing instrument trending is difficult without a logbook. • Logbooks will usually provide following: • Test usage of instrument - Date, Sample, Analyst • Maintenance and Qualification information- In-house or external, Date, Test protocol, By whom • Results - Are they Appropriate and Satisfactory? • Although information is always available elsewhere the Instrument Logbook improves traceability.

23. Data Processing Equipment Includes computers, automated tests or calibration equipment; used for collection, processing, recording, reporting, storage or retrieval of test- and/or calibration-data • Where used, requires systematic verifications of calculations and data transfers • For computer software developed by the user: • documented in detail • validated or verified as being adequate for use

24. Analytical Operations Management • Analysis planning • Standard Operating Procedures and/or Work instructions • Supplies and Services • Assuring the quality of test Results • Monitoring and evaluation • Control of data/Data integrity • Reporting & review of results • Safety

25. Analysis planning- Factors to consider • Trained and Competent Personnel • Accommodation and environmental conditions • Equipment • Test Method • Method verification and validation • Sampling • Handling of Samples

26. Trained and Competent Personnel • A key component in analytical operations. • Sufficient number, with necessary education, training, technical knowledge and experience • Areas of training relevant to the present and anticipated tasks of the laboratory. • Authorize specific personnel to perform particular types of sampling,test,verification,giving opinions and interpretations and to operate particular types of equipment. • Authourization based on competency assessment.

27. Accommodation and environmental conditions-1 • Monitor ,control and record environmental conditions as required by relevant specifications, methods and processes or where they influence the quality of results. • Specific environmental requirements - clean-room requirements • Stop test when environmental conditions jeopardize the results of the text. • Control access to testing areas • Good house keeping.

28. Accommodation and environmental conditions-2 • Suitable testing and safety equipment • Fume hoods, voltage stabilizers • Separate areas for receipt, storage and sample preparation to prevent contamination or mix-ups • Fire regulations • Flammable reagents, fuming and concentrated acids, bases, volatile amines – safe storage separately

29. Equipment • Up-to-date Work instruction on the use and maintenance of equipment • Daily checks/verifications • Operated by authourized personnel

30. Test Method • Appropriate for intended use; -Verified Compendia method -Validated in-house method • System suitability • All instructions relevant to the method readily available • Deviations documented and investigated • Unplanned deviations authourized.

31. Sampling and handling of samples • Sampling done by trained and authourized personnel -Approved sampling method . • Samples numbered for traceability. • Appropriate sample handling to maintain integrity - temperature and humidity sensitive .

32. Standard Operating Procedures (SOPs)-1 SOPs: • Purchase and receipt of consignment of materials • e.g. samples, reference material, reagents • Internal labelling, quarantine, and storage of materials • Appropriate installation of each instrument and equipment • Sampling and inspection • Testing materials, describing the methods and equipment used

33. Standard Operating Procedures (SOPs)-2 • Qualification, analytical apparatus • Calibration, maintenance, cleaning, sanitation • Safety measures • Personnel matters including -qualification, training, clothing, and hygiene • Environmental monitoring • Preparation and control of reference materials. • etc

34. Services and Supplies • All reagents and chemicals, media including solvents materials and consumables used in tests and assays, should be of appropriate quality. • Reagents should be purchased from reputable, approved suppliersand should be accompanied by the certificate of analysis, and thematerial safety data sheet, if required. • Water should be considered as a reagent. The appropriate grade for aspecific test should be used as described in the pharmacopoeias or inan approved test when available.

35. Services and Supplies • Precautions should be taken to avoid contamination during its supply, storage and distribution. • The quality of the water should be verified regularly to ensure that the various grades of water meet the appropriate specifications. • Pharmacopoeia reference substances should be employed whenavailable and appropriate for the analysis. • When a pharmacopoeia reference substance has not been established then the manufacturershould use its own reference substance(Characterized or verified with a Primary standard)

36. Monitoring and Evaluation • Monitor all inputs that impact on analytical operations -Reagents, Reference materials (availability,quality,storage) -Equipment(Analytical ,safety)- (Status, maintenance, calibration) -Method (type, suitable/appropriate -Procedures (deviations,changes,appropriate) -Personnel (training, level of competency) -Assessments (self, internal, external)

37. Control of Data/Data Integrity-1 • Calculations ,data transfer and entries are reviewed/checked. • Validation of computers or automated equipment used for data acquisition,processing,recording,reporting,storage or retrieval of test as being adequate for use • Procedures for protecting the data-including integrity and confidentiality of data entry, data storage, data transmission and data processing in place.

38. Control of Data/Data Integrity-2 The Procedure should also state and describe; • How changes are made, documented, and controlled information is maintained • How to protect and keep back-up data at all time • How to prevent unauthorized access or amendments to the data.

39. Assuring the Quality of test Results-1 Procedures for monitoring the validity of tests include; • Quality Control Checks(QCC) -Control charting(SPC) • Participation in Proficiency test and inter-laboratory comparism • Regular use of certified reference materials • Retesting of retained samples • Calibrations • etc

40. Assuring the Quality of test Results-2 • The resulting data from the procedures are recorded in such a way that trends are detectable. • When trends of data are found outside pre-determined criteria planned actions shall be taken to correct the problem and to prevent incorrect results from being reported.

41. Reporting & Review of Results-1 Analytical worksheet/Log for documentation must contain the following information: • Registration number of the sample • Page numbering including total number of pages (including annexes) • Date of the test request • Date of analysis performed • Name and signature of analyst • Description of the sample received • Reference to the specifications to which the sample was tested including limits (adding any or special methods employed) - reference number of the specifications, if available (e.g. pharmacopoeia monograph

42. Reporting & Review of Results-2 • Results obtained of tested sample • The interpretation of the results and the final conclusions, signed by each of the analysts involved and initialled by the supervisor • The identity of the test equipment used • Further comments, for example, for internal information

43. Reporting & Review of Results-3 • Detailed notes on the specifications selected and the methods of assessment used. • Whether and when portions of the sample were forwarded to other units for special tests (for example, mass spectrometry, x-ray diffraction), and the date when the results were received. • Identification number of any reference material. • If applicable, data to be attached of an instrument verification • If applicable, data to be attached of a reagent verification.

44. Reporting & Review of Results-4 • Results must be reviewed and evaluated – do they meet specification • Doubtful results should be investigated ( OOS investigation etc) • Doubtful results can be rejected only if they are clearly due to error, which has been identified. • All conclusions entered on the analytical worksheet by the analyst and initialled by the supervisor/competent personnel.

45. Reporting & Review of Results-5 • All original observations, calculations and derived data, calibration, validation and verification records etc. and final results must be retained on record for an appropriate period of time e.g.-whole length of time the drug is on the market.

46. Safety-1 Compulsory • Availability of general and specific safety instructions for all laboratory staff • written material, poster displays, audio-visual material, and occasional seminars

47. Safety-2 General rules and SOPs should include: • Availability of safety data sheets to staff prior to testing being carried out • Prohibition of smoking, eating, and drinking in the laboratory • Familiarity with the use of fire-fighting equipment, including fire extinguishers, fire blankets, and gas masks • The use of laboratory coats or other protective clothing including eye protection

48. Safety-3 • Protective clothing must be available, including eye protection, masks and gloves • Water showers should be installed • Rubber suction bulbs used on manual pipettes and siphons • Staff must be instructed in the safe handling of glassware, corrosive reagents, and solvents, and particularly in the use of safety containers or baskets to avoid spillage from containers • Warnings, precautions and instructions must be given • Safe disposal of unwanted corrosive or dangerous products by neutralization or deactivation • Safe and complete disposal of mercury and its salts

49. Safety-4 • Special handling as required for example for highly potent, infectious, or volatile substances • Full labelling of all containers of chemicals, including prominent warnings (e.g. "Poison", "Flammable", "Radiation", etc.) whenever appropriate • Adequate insulation and spark-proofing of electrical wiring and equipment, including refrigerators • Observation of safety rules in handling cylinders of compressed gases and familiarity with their colour identification codes • Awareness of avoiding solitary work in the laboratory • Provision of first-aid materials and instruction in first-aid techniques, emergency care, and use of antidotes

50. Group exercise • The QC laboratory of Sophia Pharmaceuticals ltd was recently audited by an external auditor and the following observations were made; • Though the staff are well trained , the unit had not been passing its recent proficiency tests. Its newly installed instrument has not been functioning and some records of tests conducted were not consistent with instrument print-outs. • Constitute your group into a fact finding team and make recommendations to the management of Sophia pharmaceuticals on the way forward.